Piperazine-substituted benzothiophene derivatives as antipsychotic agents

ABSTRACT

Provided is a superior, novel heterocyclic compound with improved solubility in oil such as sesame oil and benzyl benzoate, which has a broader treatment spectrum, causes less side effects, and is superior in tolerability and safety, and use thereof. A heterocyclic compound represented by the formula (I) wherein each symbol is as defined in the specification, or a salt thereof.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel heterocyclic compound and usethereof.

BACKGROUND OF THE INVENTION

As a compound having a broad treatment spectrum for central neurologicaldiseases such as schizophrenia and the like, for example, a compoundrepresented by the following formula (1) (hereinafter compound (1)) hasbeen reported (patent document 1).

wherein each symbol is as defined in patent document 1.

The above-mentioned compound (1) is an antipsychotic agent having abroader treatment spectrum as compared to conventional typicalantipsychotic agents and atypical antipsychotic agents, causing lessside effects, and superior in tolerability and safety. However, thiscompound is associated with problems in that its application to oilinjections is limited and the like, since it is poorly soluble in oilsuch as sesame oil and benzyl benzoate. Oil injections are useful ascompared to aqueous suspensions from the aspects of imparted bloodconcentration sustainability (control of diffusion in administrationsite by oily base), shortened liquid preparation time when in use(unnecessitated mixing and shaking), secured sterilization by filtration(oily base filtration), avoidance of physical stimulation atadministration site (oily base stability), improved accuracy of fillinginto injection container (container filled with oily base) and the like.

DOCUMENT LIST Patent Document

patent document 1: WO2006/112464

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The problem of the present invention is to provide a superior, novelheterocyclic compound with improved solubility in oil such as sesame oiland benzyl benzoate and use thereof.

Means of Solving the Problems

The present inventors have conducted various studies in an attempt tosolve the aforementioned problems and found that the liposolubility ofcompound (1) can be markedly improved by introducing a substituent intoa particular position on ring Q. The present invention has beencompleted based on such finding.

The present invention preferably provides a heterocyclic compound or asalt thereof shown in the following Items 1-4, a pharmaceuticalcomposition shown in the Item 5, a prophylactic and/or therapeutic agentshown in the Items 6 and 7, use shown in the Item 8, a prophylacticand/or treatment method shown in the Items 9 and 10, and a productionmethod shown in the Item 11.

Item 1. A heterocyclic compound represented by the formula (I)

whereinA is a lower alkylene group;

in the monocyclic heterocycle containing Q is

whereinR^(2′) is the following group

whereinY^(1′) is a lower alkylene group,

R^(3′) is

(1) an alkyl group,(2) a cycloalkyl group optionally substituted by a lower alkyl group,(3) a phenyl group,(4) a phenyl lower alkyl group(5) a lower alkoxy group,(6) a cycloalkyloxy group,(7) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group and a phenyl lower alkyl group,or(8) a piperidyl group optionally having a piperidyl group;

at the 3-position and the 4-position of the bicyclic heterocycleskeleton containing Z and W is —CH═CH— or

wherein R⁶ and R⁷ are the same or different and each is a hydrogen or alower alkyl group;

—W

Z—

is

wherein

R¹ is

a lower alkoxy lower alkoxy group,a phosphonooxy lower alkoxy group,a phenyl lower alkoxy lower alkoxy group,a phosphonooxy group optionally having 1 or 2 lower alkyl groups,the following group

wherein

R⁸ is

(1) an alkyl group,(2) a hydroxy-substituted lower alkyl group,(3) a cycloalkyl group,(4) a phenyl group,(5) a phenyl lower alkyl group,(6) an alkenyl group,(7) a lower alkoxy group,(8) a cycloalkyloxy group,(9) a lower alkoxy lower alkoxy group,(10) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group and a hydroxy-substituted loweralkyl group,(11) a piperidyl group optionally having a piperidyl group,(12) a piperazinyl group optionally having a lower alkyl group, or(13) the following group

wherein Aa is an alkylene group, and other symbols are as defined above,orthe following group

wherein

R⁹ is

(1) an alkyl group,(2) a hydroxy-substituted lower alkyl group,(3) a cycloalkyl group,(4) a phenyl group,(5) a phenyl lower alkyl group,(6) an alkenyl group,(7) a lower alkoxy group,(8) a cycloalkyloxy group,(9) a lower alkoxy lower alkoxy group,(10) a phenyloxy group,(11) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group and a hydroxy-substituted loweralkyl group,(12) a piperidyl group optionally having a piperidyl group,(13) a piperazinyl group optionally having a lower alkyl group, or(14) the following group

wherein Ab is an alkylene group, and other symbols are as defined above;R² is a hydrogen orthe following group

whereinY¹ is a lower alkylene group optionally substituted by(1) a lower alkoxycarbonyl group or(2) a lower alkyl group,Y² is a lower alkylene group,Y³ is a single bond or a lower alkylene group optionally substituted bya lower alkyl group,

R³ is

(1) an alkyl group,(2) a halogen-substituted lower alkyl group,(3) an alkenyl group,(4) an amino lower alkyl group,(5) a cycloalkyl group,(6) a phenyl group,(7) a phenyl lower alkyl group,(8) a piperidyl group optionally having 1 or 2 substituents selectedfrom the group consisting of a lower alkyl group and a piperidyl group,(9) a halogen-substituted piperidyl group,(10) a morpholinyl group,(11) a pyrrolidinyl group,(12) a tetrahydropyranyl group,(13) a furyl group,(14) a thienyl group,(15) a pyridyl group,(16) a pyrimidinyl group,(17) a pyridazinyl group,(18) a benzofuryl group,(19) a quinolyl group,(20) a lower alkoxycarbonyl lower alkyl group,(21) a lower alkoxy lower alkoxy lower alkyl group,(22) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,(23) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group, a cycloalkyl group, a cycloalkyllower alkyl group, a lower alkenyl group, a halogen-substituted loweralkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, alower alkoxycarbonyl lower alkyl group, a phenyl lower alkyl group, aphenyl lower alkoxy group, a furyl lower alkyl group, a pyridyl loweralkyl group, a hydroxy-substituted lower alkyl group,(24) an amino lower alkyl group optionally having a lower alkylcarbonylgroup,(25) a piperazinyl group optionally having a lower alkyl group, or(26) the following group

wherein Ac is an alkylene group, and other symbols are as defined above,

R⁴ is

(1) an alkyl group,(2) a phenyl group,(3) a phenyl lower alkyl group,(4) a halogen-substituted lower alkyl group, or(5) a cycloalkyl group,

R⁵ is

(1) a hydrogen,(2) a lower alkyl group,(3) a halogen-substituted lower alkyl group,(4) a phenyl lower alkyl group,(5) a phenyl lower alkoxy lower alkyl group,(6) a tri-lower alkylsilyl group,(7) a tetrahydropyranyl group, or(8) a phosphono group,

R¹⁰ is

(1) an alkyl group,(2) an alkenyl group,(3) a phenyl group,(4) a phenyl lower alkyl group,(5) a hydroxy-substituted lower alkyl group,(6) a cycloalkyl group,(7) an amino lower alkyl group optionally having 1 or 2 substituentsselected from the group consisting of an amino lower alkylcarbonyl groupand a lower alkylcarbonyl group,(8) a pyrrolidinyl group optionally having an amino lower alkylcarbonylgroup,(9) an alkoxy group,(10) a lower alkoxy lower alkoxy lower alkyl group,(11) a lower alkoxy lower alkoxy lower alkoxy lower alkyl group,(12) a phenyl lower alkoxy group,(13) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group, a hydroxy-substituted loweralkyl group and a phenyl lower alkyl group,(14) a morpholino group,(15) a piperazinyl group optionally having a lower alkyl group,(16) a piperidyl group optionally having a piperidyl group, or(17) a cycloalkyloxy group;provided when

is

thenR² is not a hydrogen,or a salt thereof.Item 2. The heterocyclic compound according to Item 1, which isrepresented by the formula (II)

wherein each symbol is as defined in Item 1, or a salt thereof.Item 3. The heterocyclic compound according to Item 1, which isrepresented by the formula (III)

wherein

-Wa

Za-

is

whereinR^(1a) is the following group

wherein

R^(8a) is

(1) an alkyl group,(2) a cycloalkyl group,(3) a lower alkoxy group,(4) a cycloalkyloxy group,(5) a lower alkoxy lower alkoxy group,(6) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group and a hydroxy-substituted loweralkyl group, or(7) the following group

wherein Aa′ is an alkylene group, and other symbol is as defined in Item1, orthe following group

wherein

R^(9a) is

(1) an alkyl group,(2) a hydroxy-substituted lower alkyl group,(3) a cycloalkyl group,(4) a lower alkoxy group,(5) a cycloalkyloxy group,(6) a lower alkoxy lower alkoxy group,(7) a phenyloxy group,(8) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group,(9) a piperidyl group optionally having a piperidyl group,(10) a piperazinyl group optionally having a lower alkyl group, or(11) the following group

wherein Ab′ is an alkylene group, and other symbol is as defined in Item1;

R^(2a) is

the following group

whereinY^(1a) is a lower alkylene group,Y^(2a) is a lower alkylene group,

R³ is

(1) an alkyl group,(2) a cycloalkyl group,(3) a piperidyl group optionally having 1 or 2 substituents selectedfrom the group consisting of a lower alkyl group,(4) a tetrahydropyranyl group,(5) a lower alkoxycarbonyl lower alkyl group,(6) a lower alkoxy lower alkoxy lower alkyl group(7) an amino lower alkyl group optionally having a lower alkylcarbonylgroup, or(8) the following group

wherein Ac′ is an alkylene group, Y^(1a) is a lower alkylene group andother symbols are as defined in Item 1,

R^(4a) is

(1) an alkyl group, or(2) a cycloalkyl group; andA is a lower alkylene group,or a salt thereof.Item 4. The heterocyclic compound according to Item 2, wherein R¹ isthe following group

wherein

R^(8a′) is

(1) an alkyl group,(2) a cycloalkyl group,(3) a lower alkoxy group,(4) a cycloalkyloxy group,(5) a lower alkoxy lower alkoxy group, or(6) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group and a hydroxy-substituted loweralkyl group, orthe following group

wherein

R^(9a′) is

(1) an alkyl group,(2) a hydroxy-substituted lower alkyl group,(3) a cycloalkyl group,(4) a lower alkoxy group,(5) a cycloalkyloxy group,(6) a lower alkoxy lower alkoxy group,(7) a phenyloxy group,(8) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group,(9) a piperidyl group optionally having a piperidyl group, or(10) a piperazinyl group optionally having a lower alkyl group;

R² is

the following group

whereinY^(1a) is a lower alkylene group,Y^(2a) is a lower alkylene group,

R^(3a′) is

(1) an alkyl group,(2) a cycloalkyl group(3) a piperidyl group optionally having 1 or 2 substituents selectedfrom the group consisting of a lower alkyl group,(4) a tetrahydropyranyl group,(5) a lower alkoxycarbonyl lower alkyl group,(6) a lower alkoxy lower alkoxy lower alkyl group(7) an amino lower alkyl group optionally having a lower alkylcarbonylgroup,

R^(4a) is

(1) an alkyl group, or(2) a cycloalkyl group;or a salt thereof.Item 5. A pharmaceutical composition comprising the heterocycliccompound according to Item 1 or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable diluent and/or a carrier.Item 6. A prophylactic and/or therapeutic agent for a centralneurological disease, comprising the heterocyclic compound according toItem 1 or a pharmaceutically acceptable salt thereof as an activeingredient.Item 7. The agent according to Item 6, wherein the central neurologicaldisease is selected from the group consisting of schizophrenia,treatment-resistant, refractory or chronic schizophrenia, emotionaldisturbance, psychotic disorder, mood disorder, bipolar disorder, mania,depression, endogenous depression, major depression, melancholic andtreatment-resistant depression, dysthymic disorder, cyclothymicdisorder, anxiety disorder, somatoform disorder, factitious disorder,dissociative disorder, sexual disorder, eating disorder, sleep disorder,adjustment disorder, substance-related disorder, anhedonia, delirium,Alzheimer's disease, Parkinson disease, cognitive impairment, cognitiveimpairment associated with neurodegenerative diseases, cognitiveimpairment caused by neurodegenerative diseases, cognitive impairment inschizophrenia, cognitive impairment caused by treatment-resistant,refractory or chronic schizophrenia, vomiting, motion sickness, obesity,migraine, pain, mental retardation, autistic disorder, Tourette'sdisorder, tic disorder, attention deficit hyperactivity disorder,conduct disorder and Down's syndrome.Item 8. Use of the heterocyclic compound according to Item 1 or apharmaceutically acceptable salt thereof as a medicament.Item 9. A method of preventing and/or treating a central neurologicaldisease, comprising administering the heterocyclic compound according toItem 1 or a pharmaceutically acceptable salt thereof to a human or an soanimal.Item 10. The method according to Item 9, wherein the centralneurological disease is selected from the group consisting ofschizophrenia, treatment-resistant, refractory or chronic schizophrenia,emotional disturbance, psychotic disorder, mood disorder, bipolardisorder, mania, depression, endogenous depression, major depression,melancholic and treatment-resistant depression, dysthymic disorder,cyclothymic disorder, anxiety disorder, somatoform disorder, factitiousdisorder, dissociative disorder, sexual disorder, eating disorder, sleepdisorder, adjustment disorder, substance-related disorder, anhedonia,delirium, Alzheimer's disease, Parkinson disease, cognitive impairment,cognitive impairment associated with neurodegenerative diseases,cognitive impairment caused by neurodegenerative diseases, cognitiveimpairment in schizophrenia, cognitive impairment caused bytreatment-resistant, refractory or chronic schizophrenia, vomiting,motion sickness, obesity, migraine, pain, mental retardation, autisticdisorder, Tourette's disorder, tic disorder, attention deficithyperactivity disorder, conduct disorder and Down's syndrome.Item 11. A method of producing a heterocyclic compound represented bythe formula (I)

wherein each symbol is as defined in Item 1,or a salt thereof, comprising reacting a compound represented by theformula

wherein X₁ is a halogen atom or a group that causes a substitutionreaction similar to that by a halogen atom, and other symbols are asdefined in Item 1, or a salt thereof, with a compound represented by

wherein Q is as defined in Item 1, or a salt thereof.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the transition of blood concentration of testpreparations 1, 2 and 3 after administration.

DESCRIPTION OF EMBODIMENTS

Each group shown in the aforementioned formula (I) is specifically asfollows.

Lower means, unless otherwise specified, a group having 1 to 6(preferably 1-4) carbon atoms.

As the halogen atom, a fluorine atom, a chlorine atom, a bromine atomand an iodine atom can be mentioned.

As the alkyl group, a straight chain or branched chain alkyl grouphaving a carbon number of 1-30 (preferably 1-20) can be mentioned. Morespecific examples thereof include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, isopentyl, l-ethylpropyl, neopentyl,n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl,n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 1-propylbutyl, 1,1-dimethylpentyl, 4,4-dimethylpentyl,1-pentylhexyl, n-octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl,4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1,1-dimethylheptyl,1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, n-nonyl, 3-methyloctyl,4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl,2-ethylheptyl, 6,6-dimethylheptyl, n-decyl, 1-methylnonyl,3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl,7,7-dimethyloctyl, n-undecyl, 1,1-dimethylundecyl, 4,8-dimethylnonyl,dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl,hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl,14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl,15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, icosyl,3,7,11,15-tetramethylhexadecyl, henicosyl, docosyl, tricosyl,tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl,triacontyl group and the like.

As the lower alkyl group, a linear or branched chain alkyl group havinga carbon number of 1-6 can be mentioned. More specific examples thereofinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl,1,2,2-trimethylpropyl, 3,3-dimethylbutyl group and the like.

As the alkenyl group, a straight chain or branched chain alkenyl grouphaving 1-10 double bonds and a carbon number of 2-30 can be mentioned,including both a trans form and a cis form. More specific examplesthereof include ethenyl(vinyl), 1-propenyl, 2-propenyl,l-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl,2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl,3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl,2-pentene-4-ynyl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl,3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl,1,3-hexadienyl, 1,4-hexadienyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl,hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icocenyl group andthe like.

As the lower alkenyl group, a straight chain or branched chain alkenylgroup having 1-3 double bonds and a carbon number of 2-6 can bementioned, including both a trans form and a cis form. More specificexamples thereof include vinyl, 1-propenyl, 2-propenyl,1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl,2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl, 2-pentenyl, 1-pentenyl,3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl,2-pentene-4-ynyl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3-hexenyl, 4-hexenyl,3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl,1,3-hexadienyl, 1,4-hexadienyl group and the like.

As the cycloalkyl group, cyclo C3-C20 alkyl group having 3-20 carbonatoms can be mentioned. More specific examples thereof includemonocycloalkyl such as cyclopropyl group, cyclobutyl group, cyclopentylgroup, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecylgroup, cyclododecyl group and the like, bicycloalkyl, tricycloalkyl,polycycloalkyl and the like. As the bicycloalkyl, norbornyl, pinanyl,bicyclo[2,2,2]octyl group and the like can be mentioned, and as thetricycloalkyl and polycycloalkyl, adamantyl group and the like can bementioned.

As the cycloalkyloxy group, a cyclo C3-C20 alkyl having 3-20 carbonatoms—oxy group can be mentioned. More specific examples thereof includemonocycloalkyloxy such as cyclopropyloxy group, cyclobutyloxy group,cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group,cyclooctyloxy group, cyclodecyloxy group, cyclododecyloxy group and thelike, bicycloalkyloxy, tricycloalkyloxy, polycycloalkyloxy and the like.As the cycloalkyloxy, norbornyloxy, pinanyloxy, bicyclo[2,2,2]octyloxygroup and the like can be mentioned, and as the tricycloalkyloxy andpolycycloalkyloxy, adamantyloxy group and the like can be mentioned.

As the lower alkoxy group, a straight chain or branched chain alkoxygroup having a carbon number of 1-6 can be mentioned. More specificexamples thereof include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy,neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy group and thelike.

As the halogen-substituted lower alkyl group, the aforementioned loweralkyl group, which is substituted by 1-7, more preferably 1-3, halogenatoms can be mentioned. More specific examples thereof includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl,dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl,heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl,3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl,4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl,5,5,5-trifluoropentyl, 5-chloropentyl, 6,6,6-trifluorohexyl,6-chlorohexyl, perfluorohexyl group and the like.

As the hydroxy-substituted lower alkyl group, the aforementioned loweralkyl group, which is substituted by 1-7, more preferably 1-3, hydroxygroups can be mentioned. More specific examples thereof includehydroxymethyl, 2-hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl, 5-hydroxypentyl,1-hydroxypentyl, 6-hydroxyhexyl and the like.

As the cycloalkyl lower alkyl group, the aforementioned lower alkylgroup (preferably a straight chain or branched chain alkyl group havinga carbon number of 1-6), which has 1-3, preferably 1, cycloalkyl groupmentioned above can be mentioned. It may be substituted with a loweralkyl group on the cycloalkyl group. Specific examples of the cycloalkyllower alkyl group include cyclopropylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 1-cyclobutylethyl, cyclopentylmethyl,3-cyclopentylpropyl, 4-cyclohexylbutyl, 5-cycloheptylpentyl,6-cyclooctylhexyl, 1,1-dimethyl-2-cyclohexylethyl,2-methyl-3-cyclopropylpropyl group and the like.

As the amino lower alkyl group, the aforementioned lower alkyl group(preferably a straight chain or branched chain alkyl group having acarbon number of 1-6), which has 1-5, preferably 1-3, amino group can bementioned. Specific examples of the amino lower alkyl group includeaminomethyl, diaminomethyl, triaminomethyl, 1-aminoethyl, 2-aminoethyl,1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 4-aminobutyl,5-aminopentyl, 6-aminohexyl, 1-amino-2-methylethyl, 1-aminobutyl,1-amino-2-methylpropyl, l-amino-2,2-dimethylethyl,1-amino-2-methylbutyl, 1-amino-3-methylbutyl, 1-aminohexyl,1-amino-2-methylpentyl group and the like.

As the phenyl lower alkyl group, the aforementioned lower alkyl group,which has 1-3, preferably 1, phenyl group can be mentioned. It may besubstituted with a lower alkyl group on the phenyl group. Specificexamples of the phenyl lower alkyl group include benzyl, 2-phenylethyl,1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl,2-methyl-3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl group and thelike.

As the furyl lower alkyl group, the aforementioned lower alkyl group,which has 1-3, preferably 1, furyl group can be mentioned. It may besubstituted with a lower alkyl group on the furyl group. Specificexamples of the furyl lower alkyl group include (2-furyl)methyl,2-(3-furyl)ethyl, l-(2-furyl)ethyl, 3-(3-furyl)propyl, 4-(2-furyl)butyl,5-(3-furyl)pentyl, 6-(2-furyl)hexyl, 1,1-dimethyl-2-(3-furyl)ethyl,2-methyl-3-(2-furyl)propyl group and the like.

As the pyridyl lower alkyl group, the aforementioned lower alkyl group,which has 1-3, preferably 1, pyridyl group can be mentioned. It may besubstituted with a lower alkyl group on the pyridyl group. Specificexamples of the pyridyl lower alkyl group include (4-pyridyl)methyl,1-(3-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 3-(2-pyridyl)propyl,4-(3-pyridyl)butyl, 5-(4-pyridyl)pentyl, 6-(2-pyridyl)hexyl,1,1-dimethyl-2-(3-pyridyl)ethyl, 2-methyl-3-(4-pyridyl)propyl group andthe like.

As the lower alkoxy lower alkyl group, the aforementioned lower alkylgroup (preferably a straight chain or branched chain alkyl group havinga carbon number of 1-6), which has 1-3, preferably 1, lower alkoxy group(preferably a straight chain or branched chain alkoxy group having acarbon number of 1-6) mentioned above can be mentioned. Specificexamples of the lower alkoxy lower alkyl group include methoxymethyl,ethoxymethyl, propoxymethyl, hexyloxymethyl, methoxyethyl, ethoxyethyl,propoxyethyl, isopropoxymethyl, butoxy methyl, tert-butoxy methyl,pentyloxymethyl, hexyloxymethyl group and the like.

As the lower alkoxycarbonyl group, a straight chain or branched chainalkoxycarbonyl group having a carbon number of 1-6, wherein the loweralkoxy moiety is the aforementioned lower alkoxy group can be mentioned.More specific examples thereof include methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl,n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl,isohexyloxycarbonyl, 3-methylpentyloxycarbonyl group and the like.

As the lower alkylcarbonyl group, a straight chain or branched chainalkylcarbonyl group having a carbon number of 1-6, wherein the loweralkyl moiety is the aforementioned lower alkyl group can be mentioned.More specific examples thereof include acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl and the like.

As the amino lower alkylcarbonyl group, the aforementioned loweralkylcarbonyl group having 1-5, preferably 1 or 2, amino groups, can bementioned. More specific examples thereof include aminomethylcarbonyl,2-aminoethylcarbonyl, 1-aminoethylcarbonyl, 3-aminopropylcarbonyl,4-aminobutylcarbonyl, 5-aminopentylcarbonyl, 6-aminohexylcarbonyl,1,1-dimethyl-2-aminoethylcarbonyl, 2-methyl-3-aminopropylcarbonyl groupand the like.

As the lower alkoxycarbonyl lower alkyl group, the aforementioned loweralkyl group (preferably straight chain or branched chain alkyl grouphaving a carbon number of 1-6), which has 1-3, preferably 1, loweralkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl,n-pentyloxycarbonyl, neopentyloxy, n-hexyloxycarbonyl,isohexyloxycarbonyl, 3-methylpentyloxycarbonyl group etc.) can bementioned. Specific examples of the lower alkoxycarbonyl lower alkylgroup include methoxycarbonylmethyl group, ethoxycarbonylmethyl group,propoxycarbonylmethyl group, isopropoxycarbonylmethyl group,butoxycarbonylmethyl group, isobutoxycarbonylmethyl group,sec-butoxycarbonylmethyl group, tert-butoxycarbonylmethyl group,2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group,2-propoxycarbonylethyl group, 3-methoxycarbonylpropyl group,3-ethoxycarbonylpropyl group, 4-methoxycarbonylbutyl group,4-ethoxycarbonylbutyl group and the like.

As the lower alkoxy lower alkoxy group, the aforementioned lower alkoxygroup (preferably straight chain or branched chain alkoxy group having acarbon number of 1-6), which has 1-3, preferably 1, lower alkoxy group(preferably straight chain or branched chain alkoxy group having acarbon number of 1-6) mentioned above can be mentioned. Specificexamples of the lower alkoxy lower alkoxy group include methoxymethoxy,ethoxymethoxy, propoxymethoxy, hexyloxymethoxy, methoxyethoxy,ethoxyethoxy, propoxyethoxy, isopropoxymethoxy, butoxymethoxy,tert-butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy group and thelike.

As the phenyl lower alkoxy lower alkoxy group, the aforementioned loweralkoxy lower alkoxy group having 1-3, preferably 1, phenyl group can bementioned. Specific examples of the phenyl lower alkoxy lower alkoxygroup include benzyloxymethoxy, 2-phenylethoxymethoxy,1-phenylethoxymethoxymethoxy, 3-phenylpropoxymethoxy,4-phenylbutoxymethoxy, 1,1-dimethyl-2-phenylethoxymethoxy,5-phenylpentyloxymethoxy, 6-phenylhexyloxymethoxy, 2-benzyloxyethoxy,3-benzyloxypropoxy, 4-benzyloxybutoxy, 1,1-dimethyl-2-benzyloxyethoxy,5-benzyloxypentoxy, 6-benzyloxyhexyloxy, 2-methyl-3-benzyloxypropoxygroup and the like.

As the lower alkoxy lower alkoxy lower alkyl group, the aforementionedlower alkyl group (preferably straight chain or branched chain alkylgroup having a carbon number of 1-6), which has 1-3, preferably 1, loweralkoxy lower alkoxy group mentioned above can be mentioned. Specificexamples of the lower alkoxy lower alkoxy lower alkyl group includemethoxymethoxymethyl, 3-(3-methoxypropoxy)propyl, ethoxymethoxymethyl,3-(3-ethoxypropoxy)propyl, 4-(4-ethoxybutoxy)butyl,5-(5-isopropoxypentyloxy)pentyl, 6-(6-propoxyhexyloxy)hexyl,1,1-dimethyl-2-(2-butoxyethoxy)ethyl,2-methyl-3-(3-tert-butoxypropoxy)propyl, 2-(2-pentyloxyethoxy)ethyl,hexyloxymethoxymethyl group and the like.

As the lower alkoxy lower alkoxy lower alkoxy lower alkyl group, theaforementioned lower alkoxy lower alkyl group having 1-3, preferably 1,lower alkoxy lower alkoxy group mentioned above can be mentioned.Specific examples of the lower alkoxy lower alkoxy lower alkoxy loweralkyl group include methoxyethoxyethoxyethyl, ethoxyethoxyethoxyethylgroup and the like.

As the phenyl lower alkoxy group, the aforementioned lower alkoxy grouphaving 1-3, preferably 1, phenyl group can be mentioned. Specificexamples of the phenyl lower alkoxy group include benzyloxy,2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy,1,1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy, 6-phenylhexyloxy,2-benzyloxy, 3-benzyloxy, 4-benzyloxy, 1,1-dimethyl-2-benzyloxy,5-benzyloxy, 6-benzyloxy, 2-methyl-3-benzyloxy group and the like.

As the phosphono lower alkoxy group, the aforementioned lower alkoxygroup (preferably straight chain or branched chain alkoxy group having acarbon number of 1-6), which has 1-3, preferably 1, phosphono group canbe mentioned. Specific examples of the phosphono lower alkoxy groupinclude phosphonomethoxy, phosphonoethoxy, phosphonopropoxy,phosphonobutoxy, phosphonopentyloxy, phosphonohexyloxy group and thelike.

As the piperidyl group optionally having a lower alkyl group, apiperidyl group optionally having 1-3, preferably 1, lower alkyl groupmentioned above can be mentioned. Specific examples of the piperidylgroup optionally having a lower alkyl group include piperidyl,2-methylpiperidyl, 3-methylpiperidyl, 2-ethylpiperidyl, 3-ethylpiperidylgroup and the like.

As the halogen-substituted piperidyl group, a piperidyl groupsubstituted by 1-7, more preferably 1-3, halogen atoms can be mentioned.More specific examples thereof include fluoropiperidyl,difluoropiperidyl, chloropiperidyl, dichloropiperidyl, bromopiperidyl,dibromopiperidyl group and the like.

The tri-lower alkylsilyl group is a silyl group substituted by 3 loweralkyl groups mentioned above. Specific examples thereof includetrimethylsilyl, ethyldimethylsilyl, n-propyldimethylsilyl,tert-butyldimethylsilyl, triethylsilyl, methyldiethylsilyl,dimethylethylsilyl, triisopropylsilyl group and the like.

As the lower alkylene group, a straight chain or branched chain alkylenegroup having a carbon number of 1-6 can be mentioned. More specificexamples thereof include methylene, ethylene, trimethylene,2-methyltrimethylene, 3-methyltetramethylene, 2,2-dimethyltrimethylene,1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene,pentamethylene, hexamethylene group and the like.

As the alkylene group, a straight chain or branched chain alkylene grouphaving a carbon number of 1-30 can be mentioned. More specific examplesthereof include methylene, ethylene, trimethylene, tetramethylene,hexamethylene, heptamethylene, octamethylene, decamethylene,undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene,hexadecamethylene, octadecamethylene, tricosamethylene,hexacosamethylene, triacontamethylene, 1-methylethylene,2-ethyltrimethylene, 1-methylheptamethylene, 2-methylheptamethylene,1-butylhexamethylene, 2-methyl-5-ethylheptamethylene,2,3,6-trimethylheptamethylene, 6-ethyldecamethylene,7-methyltetradecamethylene, 7-ethylhexadecamethylene,7,12-dimethyloctadecamethylene, 8,11-dimethyloctadecamethylene,7,10-dimethyl-7-ethylhexadecamethylene, 1-octadecylethylene,9,10-dioctyloctadecamethylene, 8,9-dinonylhexadecamethylene, ethenylene,1-octadecenylethylene, 7,11-octadecadienylene,7-ethenyl-9-hexadecamethylene, 7,12-dimethyl-7,11-octadecadienylene,8,11-dimethyl-7,11-octadecadienylene,9,10-dioctyl-7,11-octadecadienylene, 8,9-dinonyl-6,10-hexadecadienylenegroup and the like.

When the heterocyclic compound represented by the formula (I) is acation, it is preferably present as a salt together with anion. Theanion includes a halogen ion (e.g., Cl—, I—) and the like.

In the formula (I),

—W

Z—

is

R¹ is preferably the following group

wherein

R^(8a) is

(1) an alkyl group,(2) a cycloalkyl group,(3) a lower alkoxy group,(4) a cycloalkyloxy group,(5) a lower alkoxy lower alkoxy group,(6) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group and a hydroxy-substituted loweralkyl group, or(7) the following group

wherein Aa′ is an alkylene group and A is a lower alkylene group, orthe following group

wherein

R^(9a) is

(1) an alkyl group,(2) a hydroxy-substituted lower alkyl group,(3) a cycloalkyl group,(4) a lower alkoxy group,(5) a cycloalkyloxy group,(6) a lower alkoxy lower alkoxy group,(7) a phenyloxy group,(8) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group,(9) a piperidyl group optionally having a piperidyl group,(10) a piperazinyl group optionally having a lower alkyl group, or (11)the following group

wherein Ab′ is an alkylene group and A is a lower alkylene group,more preferably,the following group

wherein

R^(8a′) is

(1) an alkyl group,(2) a cycloalkyl group,(3) a lower alkoxy group,(4) a cycloalkyloxy group,(5) a lower alkoxy lower alkoxy group, or(6) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group and a hydroxy-substituted loweralkyl group, orthe following group

wherein

R^(9a′) is

(1) an alkyl group,(2) a hydroxy-substituted lower alkyl group,(3) a cycloalkyl group,(4) a lower alkoxy group,(5) a cycloalkyloxy group,(6) a lower alkoxy lower alkoxy group,(7) a phenyloxy group,(8) an amino group optionally having 1 or 2 substituents selected fromthe group consisting of an alkyl group,(9) a piperidyl group optionally having a piperidyl group, or(10) a piperazinyl group optionally having a lower alkyl group.

As R²,

the following group

whereinY^(1a) is a lower alkylene group,Y^(2a) is a lower alkylene group,

R^(3a) is

(1) an alkyl group,(2) a cycloalkyl group,(3) a piperidyl group optionally having 1 or 2 substituents selectedfrom the group consisting of a lower alkyl group,(4) a tetrahydropyranyl group,(5) a lower alkoxycarbonyl lower alkyl group,(6) a lower alkoxy lower alkoxy lower alkyl group,(7) an amino lower alkyl group optionally having a lower alkylcarbonylgroup, or(8) the following group

wherein Ac′ is an alkylene group, Y^(1a) is a lower alkylene group and Ais a lower alkylene group,

R^(4a) is

(1) an alkyl group, or(2) a cycloalkyl group is preferable, more preferably, R² isthe following group

whereinY^(1a) is a lower alkylene group,Y^(2a) is a lower alkylene group,

R^(3a′) is

(1) an alkyl group,(2) a cycloalkyl group,(3) a piperidyl group optionally having 1 or 2 substituents selectedfrom the group consisting of a lower alkyl group,(4) a tetrahydropyranyl group,(5) a lower alkoxycarbonyl lower alkyl group,(6) a lower alkoxy lower alkoxy lower alkyl group, or(7) an amino lower alkyl group optionally having a lower alkylcarbonylgroup,

R^(4a) is

(1) an alkyl group, or(2) a cycloalkyl group.

The heterocyclic compound represented by the formula (I) is preferably aheterocyclic compound represented by the following formula (II)

wherein each symbol is as defined in the present specification.

More preferably, it is a heterocyclic compound represented by thefollowing formula (III)

wherein each symbol is as defined In the present specification.

That is, in the formula (I),

shown at the 3-position and the 4-position of the bicyclic heterocycleskeleton containing Z and W is preferably —CH═CH—, and

in the monocyclic heterocycle containing Q is preferably

A heterocyclic compound represented by the above-mentioned formula (I)(hereinafter sometimes to be referred to as compound (I)) can beproduced by various methods. For example, it can be produced by a methodshown by the following reaction scheme.

wherein each symbol is as defined above.

In the formula (I-a), the halogen atom for X₁ is as defined above.

Examples of the group that causes a substitution reaction similar tothat by a halogen atom include a lower alkanesulfonyloxy group, anarylsulfonyloxy group, an aralkylsulfonyloxy group and the like.

Specific examples of the lower alkanesulfonyloxy group for X₁ include astraight chain or branched chain alkanesulfonyloxy group having a carbonnumber of 1-6 such as methanesulfonyloxy, ethanesulfonyloxy,n-propanesulfonyloxy, isopropanesulfonyloxy, n-butanesulfonyloxy,tert-butanesulfonyloxy, n-pentanesulfonyloxy, n-hexanesulfonyloxy groupand the like.

Examples of the arylsulfonyloxy group for X₁ include phenylsulfonyloxy,naphthylsulfonyloxy group and the like, which optionally have, as asubstituent on the phenyl ring, 1-3 groups selected from the groupconsisting of a straight chain or branched chain alkyl group having acarbon number of 1-6, a straight chain or branched chain alkoxy grouphaving a carbon number of 1-6, a nitro group and a halogen atom.Specific examples of the above-mentioned phenylsulfonyloxy groupoptionally having substituent(s) include phenylsulfonyloxy,4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy group and the like.Specific examples of the naphthylsulfonyloxy group includeα-naphthylsulfonyloxy, β-naphthylsulfonyloxy group and the like.

Examples of the aralkylsulfonyloxy group for X₁ include a straight chainor branched chain alkanesulfonyloxy group having a carbon number of 1-6and substituted by a phenyl group, which optionally have, as asubstituent on the phenyl ring, 1-3 groups selected from the groupconsisting of a straight chain or branched chain alkyl group having acarbon number of 1-6, a straight chain or branched chain alkoxy grouphaving a carbon number of 1-6, a nitro group and a halogen atom, astraight chain or branched chain alkanesulfonyloxy group having a carbonnumber of 1-6 and substituted by a naphthyl group and the like. Specificexamples of the above-mentioned alkanesulfonyloxy group substituted by aphenyl group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy,4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy,2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy,4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy group and thelike. Specific examples of the above-mentioned alkanesulfonyloxy groupsubstituted by a naphthyl group include α-naphthylmethylsulfonyloxy,β-naphthylmethylsulfonyloxy group and the like.

The reaction of a compound represented by the formula (I-a) and acompound represented by the formula (I-b) is performed without solventor in an inert solvent, in the presence or absence of a basic compound.

Examples of the inert solvent include water; ethers such as dioxane,tetrahydrofuran, diethyl ether, diethylene glycol dimethylether,ethylene glycol dimethylether and the like; aromatic hydrocarbons suchas benzene, toluene, xylene and the like; lower alcohols such asmethanol, ethanol, isopropanol and the like; ketones such as acetone,methylethyl ketone and the like; polar solvents such asN,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),hexamethylphosphoric acid triamide, acetonitrile and the like.

As the basic compound, known ones can be widely used and, for example,alkali metal hydroxide such as sodium hydroxide, potassium hydroxide,cesium hydroxide, lithium hydroxide and the like; alkali metal carbonatesuch as sodium carbonate, potassium carbonate, cesium carbonate, lithiumcarbonate and the like; alkali metal hydrogen carbonate such as lithiumhydrogen carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate and the like; alkali metal such as sodium, potassium and thelike; inorganic base such as sodium amide, sodium hydride, potassiumhydride and the like, and alkali metal alcoholates such as sodiummethoxide, sodium ethoxide, potassium methoxide, potassium ethoxide andthe like; organic base such as triethylamine, tripropylamine, pyridine,quinoline, piperidine, imidazole, N-ethyldiisopropylamine,dimethylaminopyridine, trimethylamine, dimethylaniline,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5(DBN),1,8-diazabicyclo[5.4.0]undecene-7(DBU),1,4-diazabicyclo[2.2.2]octane(DABCO) and the like.

One kind alone from these basic compounds is used, or two or more kindsthereof are mixed and used.

The amount of the basic compound to be used is generally 0.5-10-foldmol, preferably 0.5-6-fold mol, relative to the compound of the formula(I-a).

The above-mentioned reaction can be performed by adding, as necessary,an alkali metal iodide such as potassium iodide, sodium iodide and thelike as a reaction promoter.

The proportion of the compound of the formula (I-a) and the compound ofthe formula (I-b) to be used in the above-mentioned reaction scheme—1 isgenerally at least 0.5-fold mol, preferably about 0.5- to 5-fold mol, ofthe latter relative to the former.

The above-mentioned reaction is performed generally at roomtemperature—200° C., preferably room temperature—150° C., and completesin about 1-30 hr.

wherein X₂ is a hydroxyl group, a halogen atom or a group that causes asubstitution reaction similar to that by a halogen atom, and othersymbols are as defined above.

The halogen atom or group that causes a substitution reaction similar tothat by a halogen atom for X₂ is as defined above.

The reaction of a compound represented by the formula (I-c) and acompound represented by the formula (I-d) is performed under thereaction conditions similar to those of the reaction of a compoundrepresented by the formula (I-a) and a compound represented by theformula (I-b) in the aforementioned reaction scheme-1.

When compound (I-d) wherein X₂ is a hydroxyl group is used, the reactionof compound (I-c) and compound (I-d) can also be performed in a suitablesolvent, in the presence of a condensing agent.

Specific examples of the solvent to be used here include water;halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane, carbon tetrachloride and the like; aromatic hydrocarbonssuch as benzene, toluene, xylene and the like; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dimethoxyethane and the like;esters such as methyl acetate, ethyl acetate, isopropyl acetate and thelike; alcohols such as methanol, ethanol, isopropanol, propanol,butanol, 3-methoxy-1-butanol, ethylcellosolve, methylcellosolve and thelike; aprotic polar solvent such as acetonitrile, pyridine, acetone,DMF, DMSO, hexamethylphosphoric acid triamide and the like, and a mixedsolvent thereof and the like.

As the condensing agent, a mixture of azocarboxylate such asdiethylazodicarboxylate and the like and phosphorus compound such astriphenylphosphine and the like, and the like can be mentioned.

The amount of the condensing agent to be used is generally at least anequimolar amount, preferably equimole to 2-fold molar amount, relativeto compound (I-c).

The amount of compound (I-d) to be used is generally at least anequimolar amount, preferably equimole to 2-fold molar amount, relativeto compound (I-c).

This reaction preferably proceeds generally at 0-200° C., preferablyabout 0-150° C., and generally completes in about 1-10 hr.

The compound of the formula (I-a) to be used as a starting material isproduced, for example, by of the method shown in the following reactionscheme-3, and the compound represented by the formula (I-d) is produced,for example, by of the method shown in the following reaction scheme-4.

wherein X₃ is a hydroxyl group, a halogen atom or a group that causes asubstitution reaction similar to that by a halogen atom, and othersymbols are as defined above.

The halogen atom or group that causes a substitution reaction similar tothat by a halogen atom for X₃ is as defined above.

The reaction of a compound represented by the formula (I-c) and acompound represented by X₃-A-X₁ is performed under the reactionconditions similar to those of the reaction of a compound represented bythe formula (I-c) and a compound represented by the formula (I-d) in theaforementioned reaction scheme-2.

wherein X₄ is a hydroxyl group, a halogen atom or a group that causes asubstitution reaction similar to that by a halogen atom, and othersymbols are as defined above.

The halogen atom or group that causes a substitution reaction similar tothat by a halogen atom for X₄ is as defined above.

The reaction of a compound represented by the formula (I-b) and acompound represented by X₂-A-X₄ is performed under the reactionconditions similar to those of the reaction of a compound represented bythe formula (I-a) and a compound represented by the formula (I-b) in theaforementioned reaction scheme-1. Both the compound of the formula (I-b)and a compound represented by X₂-A-X₄ are easily-available knowncompounds.

wherein X₅ is a halogen atom or a group that causes a substitutionreaction similar to that by a halogen atom, and other symbols are asdefined above.

The halogen atom or group that causes a substitution reaction similar tothat by a halogen atom for X₅ is as defined above.

The reaction of a compound represented by the formula (I-e) and acompound represented by R²—X₅ is performed under the reaction conditionssimilar to those of the reaction of a compound represented by theformula (I-a) and a compound represented by the formula (I-b) in theaforementioned reaction scheme-1.

When

in the monocyclic heterocycle containing Q is

wherein R^(2′) is as defined above,the compound can be synthesized in the same manner as in thebelow-mentioned Example 383.

A compound wherein R⁸ is

wherein each symbol is as defined above,a compound wherein R⁹ is

wherein each symbol is as defined above, anda compound wherein R³ is

wherein each symbol is as defined above,can be synthesized by a combination of the methods described in thebelow-mentioned Example 14 and Example 22.

A compound (I) having a hydroxyl group on the bicyclic heterocycleskeleton containing Z and W is produced by treating a compound (I)having a methoxy group on the skeleton in a suitable solvent or withoutsolvent, in the presence of an acid.

Examples of the solvent used here include aromatic hydrocarbons such asbenzene, toluene, xylene and the like; ethers such as diethyl ether,tetrahydrofuran, dioxane, monoglyme, diglyme and the like; halogenatedhydrocarbons such as dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like; fatty acid such as acetic acid and the like;esters such as ethyl acetate, methyl acetate and the like; ketones suchas acetone, methyl ethyl ketone and the like; acetonitrile, pyridine,DMF, DMSO, hexamethylphosphoric acid triamide and a mixed solventthereof and the like.

Examples of the acid include mineral acid such as hydrobromic acid,hydrochloric acid, conc. sulfuric acid and the like, fatty acid such asformic acid, acetic acid and the like, organic acid such asp-toluenesulfonic acid and the like, Lewis acid such as aluminumchloride, zinc chloride, iron chloride, tin chloride, boron trifluoride,boron tribromide and the like, iodide such as sodium iodide, potassiumiodide and the like, a mixture of the above-mentioned Lewis acid andiodide and the like.

Such acid is preferably used in an amount of generally 0.1- to 15-foldmolar amount, preferably 0.5- to 10-fold molar amount, relative tocompound (I). When the reaction is performed without solvent, an acid isgenerally used in an excess amount.

This reaction is performed generally at 0-150° C., preferably about0-100° C., and generally completes in about 0.5-75 hr.

The starting compound used for each of the above-mentioned reactionschemes may be a preferable salt, and the object compound obtained ineach reaction may form a preferable salt. The preferable salt thereofmay be similar to the preferable salts of compound (I) shown below.

The preferable salt of compound (I) is a pharmaceutically acceptablesalt and, for example, metal salts such as alkali metal salt (e.g.,sodium salt, potassium salt etc.), alkaline earth metal salt (e.g.,calcium salt, magnesium salt etc.) and the like; salts with inorganicbases such as ammonium salt, alkali metal carbonate (e.g., lithiumcarbonate, potassium carbonate, sodium carbonate, cesium carbonateetc.), alkali metal hydrogen carbonate (e.g., lithium hydrogencarbonate, sodium hydrogen carbonate, potassium hydrogen carbonateetc.), alkali metal hydroxide (e.g., lithium hydroxide, sodiumhydroxide, potassium hydroxide, cesium hydroxide etc.) and the like;salts with organic bases such as tri(lower)alkylamine (e.g.,trimethylamine, triethylamine, N-ethyldiisopropylamine etc.), pyridine,quinoline, piperidine, imidazole, picoline, dimethylaminopyridine,dimethylaniline, N-(lower)alkyl-morpholine (e.g., N-methylmorpholineetc.), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like; salts with inorganic acids such as hydrochloride,hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the like;salts with organic acids such as formate, acetate, propionate, oxalate,malonate, succinate, fumarate, maleate, lactate, malate, citrate,tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate,p-toluenesulfonate, glutamate, pamoate and the like; and the like can bementioned.

In the following, compound (I) and a salt thereof are sometimes to begenerically referred to as the compound of the present invention.

In addition, a compound wherein a solvate (e.g., hydrate, ethanolateetc.) is added to a starting material or object compound shown in eachreaction scheme is also encompassed in each formula. As a preferablesolvate, hydrate can be mentioned.

Each object compound obtained in each of the above-mentioned reactionschemes can be isolated and purified from the reaction mixture by forexample, cooling the reaction mixture, applying an isolation operationof filtration, concentration, extraction and the like to separate acrude reaction product, and applying a general purification operationsuch as column chromatography, recrystallization and the like.

Compound (I) naturally encompasses isomers such as a geometric isomer, astereoisomer, an optical isomer and the like.

Compound (I) usable in the present invention is also encompasses samecompounds labeled with the isotope, wherein one or plural atoms is(are)replaced by one or plural atoms having a particular atomic mass or massnumber. Examples of the isotope that can be incorporated into compound(I) include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine andchlorine isotopes such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ¹⁸F, ³⁶Cl andthe like. Compound (I) labeled with particular isotope, which containsthe above-mentioned isotope and/or other isotope of other atom, forexample, compound (I) incorporating a radioactive isotope such as ³H,¹⁴C and the like, is useful for drug tissue distribution assay and/orsubstrate tissue distribution assay. Tritiated (i.e., ³H) or carbon-14(i.e., ¹⁴C) isotope are particularly preferred because of easiness ofpreparation and detectability. Furthermore, substitution with a heavierisotope such as deuterium (i.e., ²H) and the like is expected to provideimproved metabolic stability and particular therapeutic advantageattributable to increased in vivo half-time or decreased amount ofnecessary administration. An isotope-labeled compound of compound (I)can be generally prepared according to the method disclosed inWO2006/112464, by substituting a non-isotope-labeled reagent with aneasily available isotope-labeled reagent.

Compound (I) may be a pharmaceutically acceptable cocrystal or acocrystal salt. Here, the cocrystal or cocrystal salt means acrystalline substance, which is constituted from two or more kinds ofspecific solids each having different physical properties (e.g.,structure, melting point, heat of fusion and the like) at roomtemperature. The cocrystal and cocrystal salt can be produced byapplying a cocrystallization method known per se.

Compound (I) and a salt thereof are used in the form of a generalpharmaceutical preparation. Such preparation is prepared using a diluentor excipient generally used such as filler, extender, binder,humidifying agent, disintegrant, surface activating agent, lubricant andthe like. The pharmaceutical preparation can have various formsdepending on the treatment object, and representative examples includetablet, pill, powder, liquid, suspension, emulsion, granule, capsule,suppository, injection (liquid, suspension etc.) and the like.

For formulation of a tablet, various ones conventionally known as acarrier in this field can be widely used. Examples thereof includeexcipients such as lactose, sucrose, sodium chloride, glucose, urea,starch, calcium carbonate, kaolin, crystalline cellulose, silicic acidand the like, binders such as water, ethanol, propanol, simple syrup,glucose solution, starch solution, gelatin solution,carboxymethylcellulose, shellac, methylcellulose, potassium phosphate,polyvinylpyrrolidone and the like, disintegrants such as dry starch,sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acidesters, sodium lauryl sulfate, stearic acid monoglyceride, starch,lactose and the like, disintegration inhibitors such as sucrose,stearin, cacao butter, hydrogenation oil and the like, absorptionpromoters such as quaternary ammonium base, sodium lauryl sulfate andthe like, moisturizers such as glycerol, starch and the like, adsorbentsuch as starch, lactose, kaolin, bentonite, colloidal silicic acid andthe like, lubricants such as purified talc, stearate, boric acid powder,polyethylene glycol and the like; and the like. Where necessary, thetablet can take the form of a tablet having a general coating, forexample, sugar-coated tablet, gelatin-coated tablet, enteric tablet,film-coated tablet or double-compressed tablet, or multi-layer tablet.

For formulation of a pill, various ones conventionally known as acarrier in this field can be widely used. Examples thereof includeexcipients such as glucose, lactose, starch, cacao butter, hydrogenatedvegetable oil, kaolin, talc and the like, binders such as gum arabicpowder, tragacanth powder, gelatin, ethanol and the like, disintegrantssuch as laminaran, agar and the like; and the like.

For formulation of a suppository, various ones conventionally known as acarrier in this field can be widely used. Examples thereof includepolyethylene glycol, cacao butter, higher alcohol, higher alcoholesters, gelatin, semisynthetic glyceride and the like.

A capsule is prepared by a conventional method by generally mixing anactive ingredient compound with various carriers mentioned above andfilling the mixture in a hard gelatin capsule, a soft capsule and thelike.

For formulation of an injection, a liquid, an emulsion and a suspensionare preferably sterilized and isotonic with blood. For formulation intosuch form, various ones conventionally known as a diluent in this fieldcan be widely used. Examples thereof include water, ethyl alcohol,macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and thelike.

In this case, sodium chloride, glucose or glycerol in an amountsufficient for the preparation of an isotonic solution may be containedin a pharmaceutical preparation, or general solubilizing agent,buffering agent, soothing agent and the like may be further added. Wherenecessary, colorant, preservative, fragrant material, flavor, sweeteningagent and the like and other pharmaceutical products may be furthercontained in the pharmaceutical preparation.

The amount of compound (I) or a salt thereof to be contained in thepharmaceutical preparation of the present invention is not particularlylimited and is appropriately selected from a wide range. It is generallyabout 1-70 wt %, preferably about 1-30 wt %, of the preparationcomposition.

The administration method of the pharmaceutical preparation of thepresent invention is not particularly limited, and a method suitable forvarious dosage forms, age, sex and other conditions of patients, levelof disease and the like is employed for administration. For example,tablet, pill, liquid, suspension, emulsion, granule and capsule areorally administered. An injection is intravenously administered singlyor as a mixture with a general fluid replacement such as glucose, aminoacid and the like. Where necessary, it is administered singly byintramuscular, intradermal, subcutaneous or intraperitonealadministration. A suppository is intrarectally administered.

While the dose of the pharmaceutical preparation of the presentinvention is appropriately selected according to use, age, sex and otherconditions of patients, level of disease and the like, the amount of theactive ingredient compound is generally about 0.1-10 mg per day and per1 kg body weight. The active ingredient compound in the range of about1-200 mg is desirably contained in a unit administration form ofpreparation.

Effect of the Invention

The compound of the present invention has a D₂ receptor partial agonisteffect, a 5-HT_(2A) receptor antagonist effect and a serotonin uptakeinhibitory effect (or serotonin reuptake inhibitory effect).

The D₂ receptor partial agonist effect suppresses dopaminergic (DA)neurotransmission when it is enhanced, and accelerates the DAergicneurotransmission when it is lowered and thus has a function tostabilize the DA neurotransmission to a normal state (dopamine systemstabilizer). According to this function, excellent clinically improvingeffect on the abnormal DA neurotransmission (enhancement and lowering),for example, improving effect on positive and negative symptoms,improving effect on cognitive impairment, improving effect on depressivesymptom etc. are developed without causing side effects (see MichioToru: Clinical Psychiatry, vol. 46, pages 855-864 (2004), TetsuroKikuchi and Tsuyoshi Hirose: Brain Science, vol. 25, pages 579-583(2004), and Harrison, T. S. and Perry, C. M.: Drugs 64: 1715-1736,2004).

5-HT_(2A) receptor antagonist effect reduces extrapyramidal sideeffects, develops superior clinical effects, and is effective, forexample, for improvement of negative symptoms, improvement of cognitiveimpairment, improvement of depressive symptom, improvement of insomniaand the like (see Jun Ishigooka and Ken Inada: Japanese Journal ofClinical Psychopharmacology, vol. 4, pages 1653-1664 (2001), MitsukuniMurasaki: Japanese Journal of Clinical Psychopharmacology, vol. 1, pages5-22 (1998), Pullar, I. A. et al.: Eur. J. Pharmacol., 407: 39-46, 2000,and Meltzer, H. Y. et al.: Prog. Neuro-psychopharmacol. Biol. Psychiatry27: 1159-1172, 2003).

Serotonin uptake inhibitory effect (or serotonin reuptake inhibitoryeffect) is effective, for example, for improvement of depressive symptom(see Mitsukuni Murasaki: Japanese Journal of ClinicalPsychopharmacology, vol. 1, pages 5-22 (1998)).

The compound of the present invention is excellent in all of these threeeffects, or remarkably excellent in one or two of these effects.

In addition, some of the compounds of the present invention have α₁receptor antagonist effect in addition to the above-mentioned effects.The α₁ receptor antagonist effect is effective for improving positivesymptoms of schizophrenia (see Svensson, T. H.: Prog.Neuro-psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).

Therefore, the compound of the present invention has a wide treatmentspectrum for and excellent clinical effect on schizophrenia and othercentral nervous system diseases.

Accordingly, the compound, the medicament, and pharmaceuticalcomposition of the present invention are extremely effective for theimprovement of various central nervous system disorders includingschizophrenia, treatment-resistant, refractory or chronic schizophrenia,emotional disturbance, psychotic disorder, mood disorder, bipolardisorder (e.g., bipolar disorder type I and bipolar disorder type II),mania, depression, endogenous depression, major depression, melancholicand treatment-resistant depression, dysthymic disorder, cyclothymicdisorder, anxiety disorder (e.g., panic attack, panic disorder,agoraphobia, social phobia, obsessive-compulsive disorder,post-traumatic stress disorder, generalized anxiety disorder, acutestress disorder, etc.), somatoform disorder (e.g., hysteria,somatization disorder, conversion disorder, pain disorder,hypochondriasis, etc.), factitious disorder, dissociative disorder,sexual disorder (e.g., sexual dysfunction, sexual desire disorder,sexual arousal disorder, erectile dysfunction, etc.), eating disorder(e.g., anorexia nervosa, bulimia nervosa, etc.), sleep disorder,adjustment disorder, substance-related disorder (e.g., alcohol abuse,alcohol intoxication and drug addiction, stimulant intoxication,narcotism, etc.), anhedonia (e.g., anhedonia, anhedonia, iatrogenicanhedonia, anhedonia of a psychic or mental cause, anhedonia associatedwith depression, anhedonia associated with schizophrenia, etc.),delirium, cognitive impairment, cognitive impairment associated withAlzheimer's disease, Parkinson's disease, and other neurodegenerativediseases, cognitive impairment caused by Alzheimer's disease,Parkinson's disease and associated neurodegenerative diseases, cognitiveimpairment in schizophrenia, cognitive impairment caused bytreatment-resistant, refractory or chronic schizophrenia, vomiting,motion sickness, obesity, migraine, pain, mental retardation, autisticdisorder (autism), Tourette's disorder, tic disorder, attention deficithyperactivity disorder, conduct disorder, Down's syndrome and the like.

Moreover, the compound of the present invention scarcely shows sideeffects and is superior in the tolerability and safety.

Furthermore, the compound of the present invention is markedly superiorin the solubility in oil such as sesame oil and benzyl benzoate, and canbe applied to an oil injection. An oil preparation of the compound ofthe present invention shows superior blood concentration sustainability.Since the compound of the present invention changes, in blood, to acompound (compound (1)) disclosed in patent document 1, the compound ofthe present invention is also superior in the long-term maintenance ofthe blood concentration of compound (1) having desired efficacy.

In addition, the compound of the present invention is easilycrystallized, superior in the operability, and also superior in thechemical stability.

In addition, the compound (I) of the present invention can exert effectssuch as decreasing the amount of administration, improving side effects,enhancing therapeutic efficacy or the like which could not attained byconventional treatment by administering with at least one clinicallyused drug(s) selected from the group consisting of (1) mood stabilizers,(2) serotonin reuptake inhibitors, (3) norepinephrine reuptakeinhibitors, (4) serotonin and norepinephrine reuptake inhibitors and (5)antidepressants.

The present invention is explained in more detail in the following byreferring to Reference Example, Example and Experimental Example, whichare not to be construed as limitative.

Reference Example 1 Synthesis of7-(tert-butyldimethylsilanyloxy)-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one

7-(tert-Butyl-dimethylsilanyloxy)-3,4-dihydro-1H-quinolin-2-one (830 mg)was suspended in DMF (13 ml), formaldehyde (4.3 ml) and triethylamine(0.083 ml) were added, and the mixture was stirred at 80° C. overnight.After cooling to room temperature, water was added, and the mixture wasextracted with ethyl acetate, dried over sodium sulfate, and purified bymoderate-pressure silica gel column chromatography (hexane:ethylacetate-2:1) to give the title compound (36 mg) as white crystals.

Reference Example 2 Synthesis of acetic acid7-(tert-butyldimethylsilanyloxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

To a solution of7-(tert-butyldimethylsilanyloxy)-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one(37 mg) obtained in Reference Example 1 in dichloromethane were addedpyridine (0.049 ml) and acetyl chloride (0.022 ml) and the mixture wasstirred at room temperature overnight, and concentrated under reducedpressure. The residue was purified by moderate-pressure silica gelcolumn chromatography (hexane:ethyl acetate=2:1) to give the titlecompound (26 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 0.20 (s, 6H), 0.99 (s, 9H), 2.10 (s, 3H), 2.65-2.72(m, 2H), 2.83-2.89 (m, 2H), 5.89 (brs, 2H), 6.51-6.56 (m, 2H), 6.99-7.04(m, 1H)

Reference Example 3 Synthesis of7-(4-chlorobutoxy)-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one

The compound was synthesized in the same manner as in Reference Example1.

Reference Example 4 Synthesis of acetic acid7-(4-chlorobutoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

The compound was synthesized in the same manner as in Reference Example2.

¹H-NMR (CDCl₃) δ: 1.90-2.03 (m, 4H), 2.12 (s, 3H), 2.64-2.72 (m, as 2H),2.84-2.90 (m, 2H), 3.63 (t, J=6.2 Hz, 2H), 3.99 (t, J=5.7 Hz, 2H), 5.91(brs, 2H), 6.58 (dd, J=2.3, 8.2 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 7.08(d, J=8.2 Hz, 1H)

Reference Example 5 Synthesis of7-benzyloxy-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one

The compound was synthesized in the same manner as in Reference Example1.

Reference Example 6 Synthesis of tetradecanoic acid7-benzyloxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

The compound was synthesized in the same manner as in Reference Example2.

Reference Example 7 Synthesis of tetradecanoic acid7-hydroxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

To a solution of tetradecanoic acid7-benzyloxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (528 mg)obtained in Reference Example 6 in ethanol (10 ml) was added 10%palladium carbon (53 mg), and the mixture was substituted with hydrogenand stirred at room temperature for 2.5 hr. The catalyst was filteredoff, and the residue was concentrated under reduced pressure andpurified by moderate-pressure silica gel column chromatography (ethylacetate). After concentration under reduced pressure, the residue wasrecrystallized from hexane-ethyl acetate to give the title compound (209mg) as a white powder.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=6.8 Hz, 3H), 1.20-1.35 (m, 20H), 1.58-1.68(m, 2H), 2.35 (t, J=7.6 Hz, 2H), 2.65-2.71 (m, 2H), 2.82-2.88 (m, 2H),5.05 (brs, 1H), 5.90 (brs, 2H), 6.53 (dd, J=2.4, 8.1 Hz, 1H), 6.56 (d,J=2.4 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H)

Reference Example 8 Synthesis of acetic acid7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester

Acetic acid 7-(4-chlorobutoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester (339 mg) obtained in Reference Example 4 was dissolved intetrahydrofuran (10 ml), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)(709 mg) was added, and the mixture was stirred at room temperature for2 days. To the reaction mixture was added aqueous sodium hydrogencarbonate solution and the mixture was stirred, filtered, and thefiltrate was extracted with methylene chloride, dried over sodiumsulfate, and concentrated under reduced pressure, and the residue waspurified by moderate-pressure silica gel column chromatography (ethylacetate) and concentrated under reduced pressure to give the titlecompound (299 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.94-2.04 (m, 4H), 2.13 (s, 3H), 3.60-3.68 (m, 2H),4.05-4.12 (m, 2H), 6.32 (brs, 2H), 6.53 (d, J=9.5 Hz, 1H), 6.83 (dd,J=2.2, 8.6 Hz, 1H), 6.89 (d, J=2.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.63(d, J=9.5 Hz, 1H)

Reference Example 9 Synthesis of tetradecanoic acid7-hydroxy-2-oxo-2H-quinolin-1-ylmethyl ester

The compound was synthesized in the same manner as in Reference Example8.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=6.8 Hz, 3H), 1.17-1.32 (m, 20H), 1.55-1.70(m, 2H), 2.35 (t, J=7.6 Hz, 2H), 6.31 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H),6.55-6.68 (m, 1H), 6.78-6.82 (m, 1H), 6.84-6.87 (m, 1H), 7.43 (d, J=8.5Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)

Reference Example 10 Synthesis of (2-butoxy ethoxy)-acetic acid7-benzyloxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

To a solution (20 ml) of7-benzyloxy-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (760 mg)obtained in Reference Example 5, (2-butoxy ethoxy)acetic acid (473 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (771 mg) inmethylene chloride was added 4-dimethylaminopyridine (65.5 mg), and themixture was stirred at room temperature overnight. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.This was purified by moderate-pressure silica gel column chromatography(hexane:ethyl acetate=1:0 to 0:1), and concentrated under reducedpressure to give the title compound (765 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 0.90 (t, J=7.4 Hz, 3H), 1.29-1.40 (m, 2H), 1.50-1.59(m, 2H), 2.64-2.71 (m, 2H), 2.82-2.90 (m, 2H), 3.44 (t, J=6.7 Hz, 2H),3.57-3.63 (m, 2H), 3.70-3.75 (m, 2H), 4.18 (s, 2H), 5.06 (s, 2H), 5.95(brs, 2H), 6.64-6.70 (m, 2H), 7.07 (d, J=8.0 Hz, 1H), 7.30-7.45 (m, 5H)

Reference Example 11 Synthesis of (2-butoxy ethoxy)-acetic acid7-hydroxy-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

The compound was synthesized in the same manner as in Reference Example7.

¹H-NMR (CDCl₃) δ: 0.90 (t, J=7.4 Hz, 3H), 1.29-1.40 (m, 2H), 1.52-1.61(m, 2H), 2.64-2.72 (m, 2H), 2.81-2.88 (m, 2H), 3.49 (t, J=6.8 Hz, 2H),3.62-3.67 (m, 2H), 3.71-3.76 (m, 2H), 4.19 (s, 2H), 5.98 (brs, 2H),6.42-6.53 (m, 1H), 6.57 (dd, J=2.3, 8.1 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H),7.02 (d, J=8.1 Hz, 1H)

Reference Example 12 Synthesis of undec-10-enoic acid7-(4-chlorobutoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

The compound was synthesized in the same manner as in Reference Example10.

¹H-NMR (CDCl₃) δ: 1.23-1.40 (m, 10H), 1.57-1.68 (m, 2H), 1.90-2.07 (m,6H), 2.35 (t, J=7.5 Hz, 2H), 2.65-2.71 (m, 2H), 2.83-2.89 (m, 2H), 3.62(t, J=6.2 Hz, 2H), 3.98 (t, J=6.8 Hz, 2H), 4.90-4.95 (m, 1H), 4.95-5.02(m, 1H), 5.74-5.86 (m, 1H), 5.91 (brs, 2H), 6.58 (dd, J=2.3, 8.1 Hz,1H), 6.61 (d, J=2.3 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H)

Reference Example 13 Synthesis of tetradecanoic acid7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester

To a solution (5 ml) of tetradecanoic acid7-hydroxy-2-oxo-2H-quinolin-1-ylmethyl ester (208 mg) obtained inReference Example 9 in dimethylformamide were added1-bromo-4-chlorobutane (0.358 ml) and potassium carbonate (107 mg) andthe mixture was stirred at room temperature for 2 days. To the reactionmixture was added aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. This was dried over sodium sulfate,and concentrated to give a crude product. The crude product was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:1) togive the title compound (216 mg) as a white powder.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=6.9 Hz, 3H), 1.18-1.33 (m, 20H), 1.56-1.67(m, 2H), 1.94-2.04 (m, 4H), 2.36 (t, J=8.5 Hz, 2H), 3.61-3.66 (m, 2H),4.04-4.10 (m, 2H), 6.33 (brs, 2H), 6.53 (d, J=9.4 Hz, 1H), 6.82 (dd,J=2.2, 8.6 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.63(d, J=9.4 Hz, 1H)

Reference Example 14 Synthesis of (2-butoxy-ethoxy)-acetic acid7-hydroxy-2-oxo-2H-quinolin-1-ylmethyl ester

The compound was synthesized in the same manner as in Reference Example8.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=7.3 Hz, 3H), 1.22-1.38 (m, 2H), 1.48-1.59(m, 2H), 3.40-3.50 (m, 2H), 3.58-3.64 (m, 2H), 3.67-3.73 (m, 2H), 4.18(s, 2H), 6.39 (brs, 2H), 6.50 (d, J=9.4 Hz, 1H), 6.81-6.87 (m, 1H),6.90-6.94 (m, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H)

Reference Example 15 Synthesis of docosanoic acid7-(4-chlorobutoxy)-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

The compound was synthesized in the same manner as in Reference Example12.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=6.8 Hz, 3H), 1.19-1.35 (m, 36H), 1.58-1.68(m, 2H), 1.89-2.03 (m, 4H), 2.35 (t, J=7.6 Hz, 2H), 2.64-2.72 (m, 2H),2.82-2.90 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.98 (t, J=5.6 Hz, 2H), 5.91(brs, 2H), 6.58 (dd, J=2.3, 8.2 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 7.07(d, J=8.2 Hz, 1H)

Reference Example 16 Synthesis of undec-10-enoic acid7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester

The compound was synthesized in the same manner as in Reference Example8.

¹H-NMR (CDCl₃) δ: 1.20-1.39 (m, 10H), 1.57-1.67 (m, 2H), 1.95-2.05 (m,6H), 2.36 (t, J=7.5 Hz, 2H), 3.61-3.66 (m, 2H), 4.04-4.10 (m, 2H),4.90-4.95 (m, 1H), 4.95-5.01 (m, 1H), 5.74-5.85 (m, 1H), 6.33 (brs, 2H),6.52 (d, J=9.5 Hz, 1H), 6.83 (dd, J=2.2, 8.6 Hz, 1H), 6.88 (d, J=2.2 Hz,1H), 7.45 (d, J=8.6 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Reference Example 17 Synthesis of7-(4-bromobutoxy)-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one

To a solution (20 ml) of7-hydroxy-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.4 g) in DMF wereadded 1,4-dibromobutane (0.75 ml) and potassium carbonate (0.35 g) andthe mixture was stirred at 60° C. for 6 hr. After cooling to roomtemperature, water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. The organic layer was washed with water,dried over magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(dichloromethane:methanol=100:1→50:1) to give the title compound (0.6 g)as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.88-1.98 (2H, m), 2.02-2.10 (2H, m),2.47 (2H, s), 3.48 (2H, t, J=6.6 Hz), 3.97 (2H, t, J=6.0 Hz), 6.32 (1H,d, J=2.5 Hz), 6.57 (1H, dd, J=8.5, 2.5 Hz), 7.18 (1H, d, J=8.5 Hz), 8.11(1H, brs)

Reference Example 18 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one

To a solution (20 ml) of7-(4-bromobutoxy)-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.6 g)obtained in Reference Example 17 in DMF were added1-benzo[b]thiophen-4-ylpiperazine hydrochloride (0.52 g) and potassiumcarbonate (0.64 g) and the mixture was stirred at 60° C. for 6 hr. Aftercooling to room temperature, water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water, dried over magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (dichloromethane:methanol=100:1→50:1) and crystallizedfrom ethanol to give the title compound (0.33 g) as a white powder.

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.68-1.78 (2H, m), 1.80-1.90 (2H, m),2.46 (2H, s), 2.52 (2H, t, J=7.4 Hz), 2.72 (4H, m), 3.19 (4H, m), 3.98(2H, t, J=6.2 Hz), 6.30 (1H, d, J=2.5 Hz), 6.59 (1H, dd, J=8.5, 2.5 Hz),6.90 (1H, d, J=7.2 Hz), 7.18 (1H, d, J=8.5 Hz), 7.27 (1H, t, J=7.8 Hz),7.36-7.44 (2H, m), 7.55 (1H, d, J=8.1 Hz), 7.69 (1H, brs)

Reference Example 19 Synthesis of iodomethyldodecanoate

To a solution of chloromethyl dodecanoate[61413-67-0] (800 mg) indichloromethane (10 ml) and acetonitrile (10 ml) was added sodium iodide(1.45 g), and the mixture was stirred at room temperature for 3 days.The solvent was evaporated under reduced pressure, water was added, andthe mixture was extracted with dichloromethane, and dried over Na₂SO₄.The solvent was evaporated under reduced pressure to giveiodomethyldodecanoate (1.05 g).

oil: brown

¹H-NMR (CDCl₃) δ ppm: 0.88 (3H, t, J=7.0 Hz), 1.20-1.40 (16H, m),1.50-1.70 (2H, m), 2.30-2.40 (2H, m), 5.91 (2H, s)

Example 1 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one

To a solution of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one(1 g) synthesized in the same manner as in WO2006/112464 (Example 11) inDMF (10 ml) were added 37% aqueous formalin solution (3.7 ml) andtriethylamine (0.05 ml), and the mixture was heated at 80° C. for hr.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (dichloromethane:methanol=30:1) to give amixture (1 g, 3:2) of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-oneand7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one.

¹H-NMR (CDCl₃) δ: 1.68-1.80 (2H, m), 1.80-1.90 (2H, m), 2.48-2.55 (2H,m), 2.58-2.66 (2H, m), 2.66-2.78 (4H, m), 2.78-2.85 (1.2H, m), 2.86-2.92(0.8H, m), 3.14-3.25 (4H, m), 3.94-4.40 (2H, m), 5.36 (1.2H, s), 6.31(0.4H, d, J=2.3 Hz), 6.53 (0.4H, dd, J=2.4, 8.3 Hz), 6.58 (0.6H, dd,J=2.4, 8.2 Hz), 6.86 (0.6H, d, J=2.4 Hz), 6.89 (1H, d, J=7.2 Hz),7.20-7.80 (1H, m), 7.27 (1H, t, J=8.4 Hz), 7.36-7.44 (2H, m), 7.55 (1H,d, J=8.0 Hz), 7.74-7.80 (0.4H, br)

Example 2 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-benzyloxymethyl-1H-quinolin-2-one

Example 3 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-benzyloxymethoxy-quinoline

7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one(1.0 g, 2.31 mmol) synthesized in the same manner as in WO2006/112464(Example 1) was suspended in tetrahydrofuran (THF) (20 ml) and, under anitrogen atmosphere, sodium hydride (55% oil) (0.15 g, 3.44 mmol) wasadded and the mixture was stirred with heating under reflux for 30 min.The mixture was ice-cooled, benzylchloromethylether (0.48 ml, 3.46 mmol)was added, and the mixture was stirred at room temperature for 3 hr. Tothe reaction mixture was added ice water to discontinue the reaction,and the mixture was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by moderate-pressure silica gel columnchromatography (hexane:ethyl acetate=100:0 to 0:100). The first fractionwas concentrated under reduced pressure to give7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-benzyloxymethoxy-quinoline(0.15 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.73-1.83 (2H, m), 1.88-1.97 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.66-2.79 (4H, m), 3.15-3.25 (4H, m), 4.14 (2H, t, J=6.5 Hz),4.83 (2H, s), 5.78 (2H, s), 6.80 (1H, d, J=8.5 Hz), 6.89 (1H, dd, J=0.5Hz, J=7.5 Hz), 7.04 (1H, dd, J=2.5 Hz, J=9.0 Hz), 7.21 (1H, d, J=2.5Hz), 7.24-7.43 (8H, m), 7.54 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=8.0 Hz),7.94 (1H, d, J=8.5 Hz)

The second fraction was concentrated to dryness under reduced pressureto give7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-benzyloxymethyl-1H-quinolin-2-one(0.86 g) as a white amorphous solid.

¹H-NMR (CDCl₃) δ: 1.71-1.81 (2H, m), 1.85-1.94 (2H, m), 2.52 (2H, t,J=7.5 Hz), 2.64-2.78 (4H, m), 3.13-3.25 (4H, m), 4.09 (2H, t, J=6.0 Hz),4.67 (2H, s), 5.84 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.5Hz, J=8.5 Hz), 6.89 (1H, dd, J=0.5 Hz, J=7.5 Hz), 7.10 (1H, d, J=2.0Hz), 7.22-7.46 (9H, m), 7.55 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=9.5 Hz)

Example 4 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-benzyloxymethyl-3,4-dihydro-1H-quinolin-2-one

7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one(1.0 g, 2.30 mmol) synthesized in the same manner as in WO2006/112464(Example 11) was suspended in tetrahydrofuran (THF) (20 ml) and, under anitrogen atmosphere, sodium hydride (55% oil) (0.15 g, 3.44 mmol) wasadded, and the mixture was stirred with heating under reflux for 30 min.The mixture was ice-cooled, benzylchloromethylether (0.48 ml, 3.46 mmol)was added, and the mixture was stirred at room temperature for 3 hr. Tothe reaction mixture was added ice water to discontinue the reaction,and the mixture was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by moderate-pressure silica gel columnchromatography (hexane:ethyl acetate=100:0 to 0:100) and concentratedunder reduced pressure to give the title compound (yield 0.95 g, 74%) asa pale-yellow oil.

¹H-NMR (CDCl₃) δ: 1.68-1.90 (4H, m), 2.51 (2H, t, J=7.5 Hz), 2.59-2.76(6H, m), 2.78-2.85 (2H, m), 3.13-3.24 (4H, m), 3.98 (2H, t, J=6.0 Hz),4.66 (2H, s), 5.44 (2H, s), 6.08 (1H, dd, J=2.5 Hz, J=8.0 Hz), 6.89 (1H,dd, J=0.5 Hz, J=7.5 Hz), 7.00 (1H, d, J=2.5 Hz), 7.03 (1H, d, J=8.0 Hz),7.23-7.43 (8H, m), 7.55 (1H, d, J=8.0 Hz)

Example 5 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester

7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one(1.0 g, 2.30 mmol) synthesized in the same manner as in WO2006/112464(Example 11) was suspended in tetrahydrofuran (THF) (20 ml) and, under anitrogen atmosphere, sodium hydride (55% oil) (0.11 g, 2.52 mmol) wasadded, and the mixture was stirred with heating under reflux for 30 min.The mixture was cooled to −70° C., chloromethylphenylcarbonate (0.64 g,3.43 mmol) was added, and the mixture was stirred at −70° C. for 3 hr.Water was added to the reaction mixture to discontinue the reaction, andthe mixture was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by moderate-pressure silica gel columnchromatography (hexane:ethyl acetate-100:0 to 0:100) and concentratedunder reduced pressure to give the title compound (yield 0.95 g, 74%) asa colorless oil.

¹H-NMR (CDCl₃) δ: 1.69-1.91 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.64-2.77(6H, m), 2.85-2.92 (2H, m), 3.14-3.24 (4H, m), 4.01 (2H, t, J=6.5 Hz),6.06 (2H, s), 6.62 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.75 (1H, d, J=2.5 Hz),6.86-6.91 (1H, m), 7.09 (1H, d, J=8.5 Hz), 7.19-7.29 (5H, m), 7.34-7.44(3H, m), 7.55 (1H, d, J=8.0 Hz)

Example 6 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(tert-butyldimethylsilanyloxymethyl)-3,4-dihydro-1H-quinolin-2-one

To a solution (15 ml) of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one(1.5 g) synthesized in the same manner as in WO2006/112464 (Example 11)in dimethylformamide (DMF) were added 37% aqueous formalin solution (5.5ml) and a catalytic amount of triethylamine (0.08 ml) and the mixturewas stirred at 80° C. for 20 hr. After cooling to room temperature, andwater was added to the reaction mixture. The obtained insoluble materialwas collected by filtration, dried, and dissolved in dichloromethane (15ml). Imidazole (0.313 g) and tert-butylchlorodimethylsilane (0.519 g)were added, and the mixture was stirred at room temperature for 1.5 hr.Methanol was added, and the mixture was concentrated. This was purifiedby moderate-pressure silica gel column chromatography (hexane:ethylacetate=1:0 to 2:1) to give the title compound (yield 550 mg, 41.3%) asa colorless amorphous solid.

¹H-NMR (CDCl₃) δ: 0.14 (6H, s), 0.90 (9H, s), 1.70-1.80 (2H, m),1.80-1.92 (2H, m), 2.42 (2H, t, J=7.5 Hz), 2.58-2.64 (2H, m), 2.68-2.76(4H, m), 2.78-2.84 (2H, m), 3.14-3.24 (4H, m), 4.00 (2H, t, J=6.3 Hz),5.45 (2H, s), 6.58 (1H, dd, J=8.2 Hz, 2.5 Hz), 6.76 (1H, dd, J=7.6 Hz,0.6 Hz), 7.00-7.04 (2H, m), 7.27 (1H, t, J=7.8 Hz), 7.36-7.42 (2H, m),7.54 (1H, d, J=8.1 Hz)

Example 7 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 5, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.71-1.80 (2H, m), 1.85-1.95 (2H, m), 2.53 (2H, t,J=7.5 Hz), 2.65-2.76 (4H, m), 3.14-3.23 (4H, m), 4.08-4.14 (2H, m), 6.46(2H, brs), 6.53 (1H, d, J=9.5 Hz), 6.84-6.91 (2H, m), 6.97 (1H, d, J=2.0Hz), 7.18-7.30 (4H, m), 7.35-7.43 (4H, m), 7.47 (1H, d, J=8.5 Hz), 7.55(1H, d, J=8.0 Hz), 7.64 (1H, d, J=9.5 Hz)

Example 8 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(tetrahydropyran-2-yloxymethyl)-3,4-dihydro-1H-quinolin-2-one

A solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one(0.26 g), which is a mixture with7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one,was suspended in dichloromethane (10 ml), 3,4-dihydro-2H-pyran (0.08 ml)was added, p-toluenesulfonic acid hydrate (0.11 g) was added withstirring under ice-cooling, and the mixture was stirred at roomtemperature overnight. With stirring under ice-cooling, aqueous sodiumhydrogen carbonate solution was added to the reaction mixture, and themixture was extracted with dichloromethane, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography(dichloromethane:methanol-60:1) to give7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(tetrahydro-2H-pyran-2-yloxy)methyl-3,4-dihydro-1H-quinolin-2-one(180 mg).

¹H-NMR (CDCl₃) δ:1.50-1.80 (10H, m), 2.40-2.90 (6H, m), 2.72 (4H, brs),3.20 (4H, brs), 3.40-4.00 (2H, m), 4.01 (2H, t, J=6.2 Hz), 4.90-5.30(3H, m), 6.58 (1H, dd, J=8.2 Hz, 2.4 Hz), 6.90 (1H, d, J=7.6 Hz), 6.95(1H, d, J=2.4 Hz), 7.04 (1H, d, J=8.2 Hz), 7.27 (1H, t, J=7.9 Hz),7.36-7.44 (2H, m), 7.55 (1H, d, J=8.1 Hz)

Example 9 Synthesis of piperidine-1-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

To a solution (3 ml) of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester (0.29 g) synthesized in the same manner as in Example5 in THF were added piperidine (0.5 ml) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.05 ml), and the mixture wasstirred at room temperature for 16 hr. Water was added and the reactionmixture was extracted with ethyl acetate, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified bymoderate-pressure basic silica gel column chromatography (hexane:ethylacetate=1:0 to 1:1) to remove phenol, and concentrated under reducedpressure. The residue was purified by moderate-pressure silica gelcolumn chromatography (hexane:ethyl acetate=1:0 to 0:1) to give thetitle compound (yield 0.21 g, 74%) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.40-1.62 (6H, m), 1.69-1.90 (4H, m), 2.52 (2H, t,J=7.5 Hz), 2.62-2.79 (6H, m), 2.81-2.90 (2H, m), 3.13-3.26 (4H, m),3.31-3.51 (4H, m), 3.99 (2H, t, J=6.0 Hz), 5.93 (2H, s), 6.59 (1H, dd,J=2.5 Hz, 8.0 Hz), 6.78 (1H, d, J=2.5 Hz), 6.86-6.92 (1H, m), 7.05 (1H,d, J=8.5 Hz), 7.23-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, dd,J=0.5 Hz, 5.5 Hz), 7.54 (1H, d, J=8.0 Hz)

Example 10 Synthesis of piperidine-1-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

To a solution (5 ml) of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (0.44 g)synthesized in the same manner as in Example 7 in THF was addedpiperidine (0.76 ml), and the mixture was stirred at room temperaturefor 3.5 days. Water was added to the reaction mixture and the mixturewas extracted with ethyl acetate, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified bymoderate-pressure basic silica gel column chromatography (hexane:ethylacetate=1:0 to 1:1) to give the title compound (0.44 g, yieldquantitative) as a colorless amorphous solid.

¹H-NMR (CDCl₃) δ: 1.38-1.61 (6H, m), 1.72-1.82 (2H, m), 1.85-1.96 (2H,m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.80 (4H, m), 3.14-3.25 (4H, m),3.29-3.52 (4H, m), 4.10 (2H, t, J=6.0 Hz), 6.36 (2H, s), 6.52 (1H, d,J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, 8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.12(1H, t, J=2.0 Hz), 7.23-7.31 (1H, m), 7.37-7.46 (3H, m), 7.55 (1H, d,J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 11 Synthesis of benzoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Sodium hydride (55% oil) (0.15 g, 2.52 mmol) was suspended intetrahydrofuran (THF) (20 ml) and, under a nitrogen atmosphere,7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one(1.0 g, 2.30 mmol) synthesized in the same manner as in WO2006/112464(Example 11) was added, and the mixture was stirred with heating underreflux for 25 min. The mixture was cooled to 0° C., chloromethylbenzoate (0.627 g, 3.67 mmol) was added, and the mixture was stirred atroom temperature for 2.5 hr. Under ice-cooling, aqueous ammoniumchloride was added to the reaction mixture to discontinue the reaction,and the mixture was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by moderate-pressure silica gel columnchromatography (hexane:ethyl acetate=1:0 to 2:3) and concentrated underso reduced pressure to give the title compound (yield 1.132 g, 86.55%)as a colorless amorphous solid.

¹H-NMR (CDCl₃) δ: 1.64-1.75 (m, 2H), 1.77-1.86 (m, 2H), 2.44-2.51 (m,2H), 2.61-2.77 (m, 6H), 2.87-2.93 (m, 2H), 3.11-3.22 (m, 4H), 3.97 (t,J=6.3 Hz, 2H), 6.17 (brs, 2H), 6.61 (dd, J=2.4, 8.3 Hz, 1H), 6.74 (d,J=2.4 Hz, 1H), 6.84-6.91 (m, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.27 (dd,=7.7, 7.7 Hz, 1H), 7.37-7.46 (m, 4H), 7.51-7.58 (m, 2H), 8.00-8.07 (m,2H)

Example 12 Synthesis of benzoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.67-1.78 (m, 2H), 1.81-1.91 (m, 2H), 2.45-2.53 (m,2H), 2.63-2.75 (m, 4H), 3.11-3.22 (m, 4H), 4.07 (t, J=6.3 Hz, 2H), 6.56(d, J=9.5 Hz, 1H), 6.59 (brs, 2H), 6.84 (dd, J=2.2, 8.6 Hz, 1H),6.86-6.90 (m, 1H), 6.98 (d, J=2.2 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H),7.37-7.44 (m, 4H), 7.46 (d, J=8.6 Hz, 1H), 7.51-7.59 (m, 2H), 7.65 (d,J=9.5 Hz, 1H), 8.02-8.07 (m, 2H)

Example 13 Synthesis of cyclopentanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

To a solution (20 ml) of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one(962 mg, 2.066 mmol) synthesized in the same manner as in Example 1,cyclopentanecarboxylic acid (0.448 ml, 4.13 mmol),2-chloro-1,3-dimethylimidazolium chloride (768 mg, 4.55 mmol) inmethylene chloride was added triethylamine (1.267 ml, 9.09 mmol), andthe mixture was stirred at room temperature for 1 hr.2-Chloro-1,3-dimethylimidazolium chloride (768 mg, 4.55 mmol) was added,and the mixture was heated under reflux for 1 hr. After cooling to roomtemperature, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. This was purified by moderate-pressurebasic silica gel column (hexane:ethyl acetate=1:3) and concentratedunder reduced pressure to give the title compound (yield 261 mg, 22.49%)as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.50-1.63 (m, 2H), 1.63-1.79 (m, 4H), 1.79-1.95 (m,6H), 2.52 (t, J=7.4 Hz, 2H), 2.64-2.83 (m, 7H), 2.83-2.89 (m, 2H),3.13-3.25 (m, 4H), 3.98 (d, J=6.2 Hz, 2H), 5.91 (brs, 2H), 6.57-6.61 (m,2H), 6.89 (d, J=7.6 Hz, 1H), 7.04-7.09 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz,1H), 7.36-7.43 (m, 2H), 7.54 (d, J=8.0 Hz, 1H)

Example 14 Synthesis of cyclohexanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

To a solution (15 ml) of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one(550 mg) synthesized in the same manner as in Example 1 indichloromethane was added pyridine (0.287 ml), cyclohexanecarbonylchloride (0.158 ml) with stirring under ice-cooling and the mixture wasstirred at room temperature overnight. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by moderate-pressure silica gelcolumn chromatography (hexane:ethyl acetate=1:0 to 1:3), andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography, and concentrated to dryness underreduced pressure to give the title compound (yield 172 mg, 25.3%) as acolorless amorphous solid.

¹H-NMR (CDCl₃) δ:1.15-1.32 (m, 3H), 1.40-1.53 (m, 2H), 1.57-1.65 (m,1H), 1.68-1.79 (m, 4H), 1.81-1.96 (m, 4H), 2.36 (tt, J=3.6, 11.2 Hz,1H), 2.52 (t, J=7.5 Hz, 2H), 2.65-2.76 (m, 6H), 2.83-2.90 (m, 2H),3.15-3.24 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.91 (brs, 2H), 6.56-6.63 (m,2H), 6.87-6.92 (m, 1H), 7.05-7.09 (m, 1H), 7.27 (dd, J=7.7, 7.7 Hz, 1H),7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 15 Synthesis of 2,2-dimethylpropionic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.22 (s, 9H), 1.68-1.90 (m, 4H), 2.48-2.55 (m, 2H),2.65-2.76 (m, 6H), 2.82-2.89 (m, 2H), 3.13-3.24 (m, 4H), 3.97 (t, J=6.2Hz, 2H), 5.90 (s, 2H), 6.57-6.62 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d,J=8.1 Hz, 1H), 7.27 (dd, J=7.7. 7.7 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d,J=8.1 Hz, 1H)

Example 16 Synthesis of N-butyl-N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: {0.82 (t, J=7.0 Hz), 0.94 (t, J=7.0 Hz) total 3H(1:1)}, 1.14-1.58 (4H, m), 1.64-1.91 (4H, m), 2.52 (2H, t, J=7.5 Hz),2.63-2.78 (6H, m), 2.81-2.96 (5H, m), 3.13-3.33 (6H, m), 3.99 (2H, t,J=6.0 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.0 Hz, 8.0 Hz), 6.77 (1H, d,J=6.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.0 Hz), 7.27 (1H, dd,J=8.0 Hz, 8.0 Hz), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=7.5 Hz), 7.55(1H, d, J=8.0 Hz)

Example 17 Synthesis of N-decylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=7.0 Hz), 1.16-1.34 (14H, m), 1.42-1.53(2H, m), 1.69-1.89 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.62-2.77 (6H, m),2.80-2.88 (2H, m), 3.12-3.25 (6H, m), 4.00 (2H, t, J=6.0 Hz), 4.85 (1H,t, J=5.5 Hz), 5.91 (2H, s), 6.59 (1H, dd, J=2.0 Hz, 8.0 Hz), 6.79 (1H,d, J=2.0 Hz), 6.86-6.91 (1H, m), 7.05 (1H, d, J=8.0 Hz), 7.27 (1H, dd,J=8.0 Hz, 8.0 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0 Hz)

Example 18 Synthesis of 2,2-dimethylpropionic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.20 (s, 9H), 1.71-1.81 (m, 2H), 1.85-1.95 (m, 2H),2.54 (t, J=7.5 Hz, 2H), 2.67-2.78 (m, 4H), 3.15-3.24 (m, 4H), 4.06 (t,J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.80 (d, J=2.2Hz, LH), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.88-6.91 (m, 1H), 7.27 (dd,J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d,J=8.1 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)

Example 19 Synthesis of butyric acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.96 (t, J=7.4 Hz, 3H), 1.63-1.79 (m, 4H), 1.80-1.90(m, 2H), 2.35 (t, J=7.4 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.64-2.77 (m,6H), 2.82-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.99 (t, J=6.2 Hz, 2H), 5.92(brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H),7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.44 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 20 Synthesis of butyric acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.94 (t, J=7.4 Hz, 3H), 1.62-1.72 (m, 2H), 1.72-1.82(m, 2H), 1.86-1.96 (m, 2H), 2.35 (t, J=7.4 Hz, 2H), 2.54 (t, J=7.4 Hz,2H), 2.65-2.78 (m, 4H), 3.13-3.25 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34(brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H),6.86-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45(d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)

Example 21 Synthesis of dodecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=6.8 Hz), 1.20-1.36 (16H, m), 1.58-1.69(2H, m), 1.69-1.80 (2H, m), 1.80-1.90 (2H, m), 2.36 (2H, t, J=7.6 Hz),2.52 (2H, t, J=7.4 Hz), 2.64-2.76 (6H, m), 2.82-2.90 (2H, m), 3.14-3.26(4H, br), 3.98 (2H, t, J=6.2 Hz), 5.92 (2H, brs), 6.56-6.64 (2H, m),6.89 (1H, d, J=7.6 Hz), 7.07 (1H, d, J=8.1 Hz), 7.27 (1H, t, J=7.8 Hz),7.40 (2H, dd, J=5.6, 12.6 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 22 Synthesis of dodecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

To a solution (5 ml) of dodecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester (150 mg) synthesized in the same manner as in Example 21 in THFwas added trifluoroacetic acid (TFA) (0.11 ml), then to a solution (3ml) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.27 g) in THEwas added, and the mixture was stirred at room temperature for 3 days.To the reaction mixture were added water and sodium carbonate, and themixture was extracted with dichloromethane, dried over sodium sulfate,and concentrated under reduced pressure. The residue was purified bypreparative thin layer chromatography (ethyl acetate) to give the titlecompound (yield 50 mg, 33.4%) as a brown oil.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=6.9 Hz), 1.20-1.34 (16H, m), 1.55-1.68(2H, m), 1.72-1.82 (2H, m), 1.85-1.94 (2H, m), 2.36 (2H, t, J=7.5 Hz),2.50-2.60 (2H, m), 2.73 (4H, m), 3.20 (4H, m), 4.08 (2H, t, J=5.3 Hz),6.34 (2H, brs), 6.52 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.5 Hz),6.86-6.92 (2H, m), 7.24-7.30 (1H, m), 7.40 (2H, dd, J=5.6, 10.9 Hz),7.45 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 23 Synthesis of hexadecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=6.8, 3H), 1.18-1.34 (m, 26H), 1.57-1.80 (m,4H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.53 (t, J=7.5 Hz, 2H),2.63-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.15-3.25 (m, 2H), 3.98 (t, J=6.2Hz, 2H), 5.92 (brs, 2H), 6.59 (dd, J=2.3, 8.1 Hz, 1H), 6.62 (d, J=2.3Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 24 Synthesis of octanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.86 (t, J=6.9 Hz, 3H), 1.19-1.35 (m, 8H), 1.59-1.68(m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.53 (t, J=7.5 Hz, 2H), 2.65-2.78 (m, 6H), 2.83-2.89 (m, 2H), 3.14-3.24(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1Hz, 1H), 6.62 (d, J=2.2, 1H), 6.88-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H),7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.1 Hz, 1H)

Example 25 Synthesis of phenylacetic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.62-1.86 (m, 4H), 2.52 (t, J=7.4 Hz, 2H), 2.65-2.77(m, 6H), 2.82-2.88 (m, 2H), 3.14-3.25 (m, 4H), 3.68 (s, 2H), 3.85 (t,J=6.2 Hz, 2H), 5.94 (brs, 2H), 6.51 (d, J=2.3 Hz, 1H), 6.58 (dd, J=2.3,8.2 Hz, 1H), 6.88-6.92 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.23-7.34 (m,6H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.1 Hz, 1H)

Example 26 Synthesis of phenylacetic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.65-1.88 (m, 4H), 2.52 (t, J=7.4 Hz, 2H), 2.64-2.78(m, 4H), 3.14-3.25 (m, 4H), 3.67 (s, 2H), 3.87 (t, J=6.2 Hz, 2H), 6.35(brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.72 (d, J=2.1 Hz, 1H), 6.82 (dd,J=2.1, 8.6 Hz, 1H), 6.84-6.92 (m, 1H), 7.22-7.31 (m, 6H), 7.37-7.46 (m,3H), 7.55 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)

Example 27 Synthesis of N-butylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.5 Hz), 1.24-1.40 (2H, m), 1.43-1.53(2H, m), 1.69-1.80 (2H, m), 1.81-1.91 (2H, m), 2.53 (2H, t, J=7.5 Hz),2.64-2.77 (6H, m), 2.82-2.89 (2H, m), 3.13-3.27 (6H, m), 4.00 (2H, t,J=6.0 Hz), 4.74-4.82 (1H, m), 5.92 (2H, s), 6.59 (1H, dd, J=2.0 Hz, 8.0Hz), 6.79 (1H, d, J=6.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=8.0Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz),7.55 (1H, d, J=8.0 Hz)

Example 28 Synthesis of N,N-dibutylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.80 (3H, t, J=7.0 Hz), 0.93 (3H, t, J=7.0 Hz),1.13-1.58 (8H, m), 1.68-1.90 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.62-2.78(6H, m), 2.80-2.89 (2H, m), 3.09-3.30 (8H, m), 3.98 (2H, t, J=6.0 Hz),5.93 (2H, s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.76 (1H, d, J=2.5 Hz),6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38(1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 29 Synthesis of N-cyclohexylmethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.81-0.98 (2H, m), 1.07-1.30 (3H, m), 1.36-1.50 (1H,m), 1.59-1.80 (7H, m), 1.81-1.91 (2H, m), 2.53 (2H, t, J=7.5 Hz),2.63-2.78 (6H, m), 2.81-2.89 (2H, m), 3.05 (2H, J=6.5 Hz), 3.14-3.24(4H, m), 4.00 (2H, t, J=6.0 Hz), 4.84 (1H, t, J=5.5 Hz), 5.92 (2H, s),6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.80 (1H, d, J=2.0 Hz), 6.87-6.92 (1H,m), 7.05 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.37-7.44 (2H, m), 7.55(1H, d, J=8.0 Hz)

Example 30 Synthesis of octanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.85 (t, J=6.9 Hz, 3H), 1.16-1.33 (m, 8H), 1.57-1.68(m, 2H), 1.74-1.96 (m, 4H), 2.36 (t, J=7.5 Hz, 2H), 2.52-2.63 (m, 2H),2.69-2.85 (m, 4H), 3.15-3.29 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs,2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.1, 8.6 Hz, 1H), 6.86-6.92 (m,2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.42 (m, 2H), 7.45 (d, J=8.6 Hz,1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Example 31 Synthesis of icosanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

To a solution (6 ml) of arachidic acid (1048 mg, 3.35 mmol) in1,2-dichloroethane was added thionyl chloride (1.217 ml, 16.77 mmol),and the mixture was heated under reflux, and concentrated under reducedpressure to give acid chloride. To a solution (15 ml) of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one(781 mg, 1.677 mmol) synthesized in the same manner as in Example 1 indichloromethane were added pyridine (1.357 ml, 16.77 mmol) and theabove-mentioned acid chloride, and the mixture was stirred at roomtemperature for 3 hr. The organic layer was dried over sodium sulfate,and concentrated under reduced pressure. The residue was purified bymoderate-pressure silica gel column chromatography (hexane:ethylacetate=1:0 to 1:1), and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography(hexane:ethyl acetate=1:0 to 1:1), and concentrated to dryness underreduced pressure to give the title compound (yield 856 mg, 67%) as acolorless oil.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=6.8 Hz, 3H), 1.19-1.35 (m, 32H), 1.57-1.68(m, 2H), 1.69-1.79 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.6 Hz, 2H),2.52 (t, J=7.5 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.14-3.25(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.3, 8.1Hz, 1H), 6.62 (d, J=2.3 Hz, 1), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz,1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.1 Hz,1H)

Example 32 Synthesis of cyclohexanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.14-1.31 (m, 3H), 1.39-1.52 (m, 2H), 1.54-1.65 (m,1H), 1.67-1.82 (m, 4H), 1.84-1.95 (m, 4H), 2.31-2.41 (m, 1H), 2.54 (t,J=7.6 Hz, 2H), 2.65-2.79 (m, 4H), 3.13-3.25 (m, 4H), 4.07 (t, J=6.2 Hz,2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.86 (m, 2H), 6.89 (d,J=7.6 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.47 (m, 3H), 7.55 (d,J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Example 33 Synthesis of (Z)-octadec-9-enoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ:0.87 (t, J=6.8 Hz, 3H), 1.20-1.36 (m, 20H), 1.58-1.68(m, 2H), 1.69-1.79 (m, 2H), 1.80-1.90 (m, 2H), 1.93-2.07 (m, 4H), 2.36(t, J=7.5 Hz, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.79 (m, 6H), 2.83-2.90(m, 2H), 3.14-3.25 (m, 4H), 3.99 (t, J=6.3 Hz, 2H), 5.28-5.40 (m, 2H),5.92 (brs, 2H), 6.60 (dd, J=2.3. 8.1 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H),6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H),7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 34 Synthesis of N-decylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized inthe same manner as in Example 7 and in the same manner as in Example 9,the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=7.0 Hz), 1.16-1.35 (12H, m), 1.42-1.53(4H, m), 1.72-1.83 (2H, m), 1.86-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz),2.67-2.80 (4H, m), 3.13-3.28 (6H, m), 4.11 (2H, t, J=6.0 Hz), 4.87 (1H,t, J=5.5 Hz), 6.33 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0Hz, J=8.5 Hz), 6.87-6.92 (1H, m), 7.16 (1H, d, J=1.5 Hz), 7.24-7.30 (1H,m), 7.36-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 35 Synthesis of N-butylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.91 (3H, t, J=7.5 Hz), 1.28-1.39 (2H, m), 1.43-1.53(2H, m), 1.73-1.82 (2H, m), 1.87-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz),2.67-2.78 (4H, m), 3.15-3.24 (6H, m), 4.11 (2H, t, J=6.0 Hz), 4.88 (1H,t, J=5.5 Hz), 6.32 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.15 (1H, d, J=1.5 Hz), 7.24-7.30(1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5Hz)

Example 36 Synthesis of N-butyl-N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: {0.87 (t, J=7.5 Hz), 0.94 (t, J=7.5 Hz) total 3H(1:1)}, 1.08-1.19 (1H, m), 1.26-1.43 (2H, m), 1.47-1.57 (1H, m),1.72-1.83 (2H, m), 1.85-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.79(4H, m), {2.82 (s), 2.92 (s) total 3H (1:1)}, 3.12-3.25 (5H, m), 3.30(1H, t, J=7.5 Hz), 4.10 (2H, t, J=6.0 Hz), 6.35 (2H, s), 6.52 (1H, dd,J=1.5 Hz, J=9.5 Hz), 6.83 (1H, dd, J=1.5 Hz, J=8.5 Hz), 6.89 (1H, d,J=7.5 Hz), 7.10 (1H, d, J=16.5 Hz), 7.25-7.30 (1H, m), 7.37-7.45 (3H,m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 37 Synthesis of cyclopentanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

To a solution (10 ml) of cyclopentanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester (252 mg) synthesized in the same manner as in Example 13 in THFwas added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (509 mg), andthe mixture was stirred at room temperature stirred for 2 days. To thereaction mixture were added water and sodium carbonate, and the mixturewas extracted with dichloromethane, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified bymoderate-pressure silica gel column chromatography (hexane:ethylacetate=1:0 to 0:1) and further by NH silica gel column chromatography(hexane:ethyl acetate=1:0 to 0:1) to give the title compound (yield 38mg, 15%) as a colorless amorphous solid.

¹H-NMR (CDCl₃) δ:1.50-1.62 (m, 2H), 1.62-1.95 (m, 10H), 2.54 (t, J=7.5Hz, 2H), 2.67-2.83 (m, 5H), 3.14-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H),6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.86 (m, 2H), 6.89 (d,J=7.4 Hz, 1H), 7.27 (t, J=7.9, 7.9 Hz, 1H), 7.37-7.47 (m, 3H), 7.55 (d,J=7.9 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Example 38 Synthesis of N-octadecylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=7.0 Hz), 1.13-1.34 (30H, m), 1.43-1.53(2H, m), 1.73-1.83 (2H, m), 1.85-1.965 (2H, m), 2.54 (2H, t, J=7.5 Hz),2.66-2.79 (4H, m), 3.13-3.25 (6H, m), 4.12 (2H, t, J=6.0 Hz), 4.85 (1H,t, J=5.5 Hz), 6.33 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.16 (1H, d, J=1.5 Hz), 7.24-7.30(1H, m), 7.36-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5Hz)

Example 39 Synthesis of (Z)-octadec-9-enoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (t, J=6.8 Hz, 3H), 1.18-1.35 (m, 20H), 1.57-1.68(m, 2H), 1.72-1.82 (m, 2H), 1.86-2.04 (m, 6H), 2.36 (t, J=7.4 Hz, 2H),2.52 (t, J=7.4 Hz, 2H), 2.67-2.79 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 5.26-5.39 (m, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz,1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (t, J=7.9 Hz,1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H),7.62 (d, J=9.5 Hz, 1H)

Example 40 Synthesis of 2-pentylheptanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 31, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.85 (t, 6H), 1.17-1.31 (m, 12H), 1.37-1.49 (m, 2H),1.55-1.78 (m, 4H), 1.79-1.89 (m, 2H), 2.32-2.41 (m, 1H), 2.52 (t, J=7.4Hz, 2H), 2.64-2.77 (m, 6H), 2.82-2.89 (m, 2H), 3.13-3.24 (m, 4H), 3.97(t, J=6.2 Hz, 2H), 5.94 (brs, 2H), 6.59 (dd, J=2.3, 8.2 Hz, 1H), 6.63(d, J=2.3 Hz, 1H), 6.87-6.92 (m, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.27 (dd,J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H),

Example 41 Synthesis of icosanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ:0.88 (t, J=6.8 Hz, 3H), 1.18-1.33 (m, 32H), 1.58-1.67(m, 2H), 1.72-1.82 (m, 2H), 1.86-1.96 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.54 (t, J=7.5 Hz, 2H), 2.67-2.77 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.1,8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.36-7.43(m, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5Hz, 1H)

Example 42 Synthesis of hexadecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (t, J=6.8 Hz, 3H), 1.18-1.32 (m, 24H), 1.58-1.67(m, 2H), 1.72-1.95 (m, 4H), 2.36 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5 Hz,2H), 2.66-2.78 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.34(brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H),6.86-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.36-7.43 (m, 2H), 7.44(d, J=9.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Example 43 Synthesis of N-pentadecylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized inthe same manner as in Example 7 and in the same manner as in Example 9,the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=7.0 Hz), 1.16-1.33 (24H, m), 1.42-1.53(2H, m), 1.72-1.83 (2H, m), 1.86-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz),2.67-2.78 (4H, m), 3.14-3.24 (6H, m), 4.11 (2H, t, J=6.0 Hz), 4.86 (1H,t, J=5.5 Hz), 6.33 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.39 (1H, d, J=−1.5 Hz),7.24-7.29 (1H, m), 7.37-7.44 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H,d, J=9.5 Hz)

Example 44 Synthesis of N-methyl-N-octadecylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=7.0 Hz), 1.01-1.32 (30H, m), 1.33-1.43(1H, m), 1.47-1.58 (1H, m), 1.72-1.83 (2H, m), 1.85-1.95 (2H, m), 2.54(2H, t, J=7.5 Hz), 2.66-2.78 (4H, m), {2.82 (s), 2.93 (s) total 3H(1:1)}, 3.12-3.24 (5H, m), 3.25-3.32 (1H, m), 4.09 (2H, t, J=5.5 Hz),6.36 (2H, s), 6.52 (1H, dd, J=2.0 Hz, J=9.5 Hz), 6.83 (1H, d, J=8.5 Hz),6.89 (1H, d, J=7.5 Hz), 7.10 (1H, d, J=17.5 Hz), 7.24-7.30 (1H, m),7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.66 (1H, dd, J=4.0 Hz, J=9.5Hz)

Example 45 Synthesis of N,N-dibutylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized inthe same manner as in Example 7 and in the same manner as in Example 9,the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.72 (3H, t, J=7.5 Hz), 0.93 (3H, t, J=7.5 Hz),1.06-1.19 (2H, m), 1.24-1.42 (4H, m), 1.48-1.59 (2H, m), 1.72-1.83 (2H,m), 1.85-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.65-2.83 (4H, m), 3.12(2H, t, J=7.5 Hz), 3.15-3.23 (4H, m), 3.26 (2H, J=7.5 Hz), 4.09 (2H, t,J=6.0 Hz), 6.36 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz,J=8.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.07 (1H, d, J=2.0 Hz), 7.25-7.31(1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5Hz)

Example 46 Synthesis of N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.70-1.80 (2H, m), 1.81-1.91 (2H, m), 2.53 (2H, t,J=7.5 Hz), 2.63-2.77 (6H, m), 2.79-2.89 (5H, m), 3.14-3.24 (4H, m), 4.00(2H, t, J=6.0 Hz), 4.75 (1H, d, J=4.0 Hz), 5.92 (2H, s), 6.59 (1H, dd,J=2.5 Hz, 8.5 Hz), 6.78 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06(1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H,d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 47 Synthesis of N,N-dimethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.79 (2H, m), 1.81-1.90 (2H, m), 2.52 (2H, t,J=7.5 Hz), 2.64-2.77 (6H, m), 2.83-2.91 (2H, m), 2.88 (3H, s), 2.95 (3H,s), 3.14-3.24 (4H, m), 4.00 (2H, t, J=6.5 Hz), 5.92 (2H, s), 6.59 (1H,dd, J=2.5 Hz, 8.5 Hz), 6.78 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz),7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.42(1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 48 Synthesis of octadecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

To a solution (20 ml) of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one(640 mg, 2.066 mmol) synthesized in the same manner as in Example 1,stearic acid (587 mg, 2.062 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (395 mg,2.062 mmol) in methylene chloride was added 4-dimethylaminopyridine(33.6 mg, 0.275 mmol), and the mixture was stirred at room temperatureovernight. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. This was purified by moderate-pressuresilica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) andfurther by basic silica gel column chromatography (hexane:ethylacetate-1:0 to 0:1) and concentrated under reduced pressure to give thetitle compound (yield 649 mg, 64.5%) as a colorless oil.

¹H-NMR (CDCl₃) δ:0.88 (t, J=6.9 Hz, 3H), 1.18-1.35 (m, 28H), 1.59-1.68(m, 2H), 1.69-1.79 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.52 (t, J=7.4 Hz, 2H), 2.65-2.76 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.24(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz,1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz,1H)

Example 49 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester ethyl ester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.2 Hz), 1.70-1.80 (2H, m), 1.80-1.90(2H, m), 2.52 (2H, t, J=7.4 Hz), 2.65-2.73 (2H, m), 2.72 (4H, m), 2.86(2H, t, J=7.2 Hz), 3.14-3.24 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.25 (2H,q, J=7.2 Hz), 5.94 (2H, brs), 6.59 (1H, dd, J=2.3, 8.3 Hz), 6.69 (1H, d,J=2.3 Hz), 6.90 (1H, d, J=7.6 Hz), 7.06 (1H, d, J=8.1 Hz), 7.27 (1H, t,J=7.8 Hz), 7.37-7.43 (2H, m), 7.55 (1H, d, J=8.1 Hz)

Example 50 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester ethyl ester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.1 Hz), 1.72-1.84 (2H, m), 1.84-1.96(2H, m), 2.56 (2H, t, J=7.4 Hz), 2.70-2.80 (4H, m), 3.16-3.26 (4H, m),4.10 (2H, t, J=6.2 Hz), 4.26 (2H, q, J=7.1 Hz), 6.35 (2H, brs), 6.50(1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.88-6.95 (2H, m), 7.27(1H, t, J=7.8 Hz), 7.37-7.41 (2H, m), 7.44 (1H, d, J=8.6 Hz), 7.55 (1H,d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)

Example 51 Synthesis of N-ethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.14 (3H, t, J=7.0 Hz), 1.69-1.80 (2H, m), 1.81-1.90(2H, m), 2.52 (2H, t, J=7.5 Hz), 2.61-2.79 (6H, m), 2.81-2.90 (2H, m),3.09-3.31 (6H, m), 4.00 (2H, t, J=6.0 Hz), 4.73-4.84 (1H, m), 5.92 (2H,s), 6.59 (1H, dd, J=2.5 Hz, 8.5 Hz), 6.79 (1H, d, J=2.0 Hz), 6.90 (1H,d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.37-7.44 (2H,m), 7.55 (1H, d, J=8.0 Hz)

Example 52 Synthesis of N,N-diethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.00-1.19 (6H, m), 1.66-1.79 (2H, m), 1.80-1.91 (2H,m), 2.52 (2H, t, J=7.5 Hz), 2.63-2.78 (6H, m), 2.82-2.90 (2H, m),3.14-3.38 (8H, m), 3.99 (2H, t, J=6.0 Hz), 5.93 (2H, s), 6.59 (1H, dd,J=2.5 Hz, 8.5 Hz), 6.77 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06(1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H,d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 53 Synthesis of N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.73-1.84 (2H, m), 1.85-1.96 (2H, m), 2.55 (2H, t,J=7.5 Hz), 2.66-2.78 (4H, m), {2.82 (s), 2.84 (s) total 3H (1:1)},3.13-3.26 (4H, m), 4.12 (2H, t, J=6.0 Hz), 4.76-4.86 (1H, m), 6.33 (2H,s), 6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H,d, J=7.5 Hz), 7.15 (1H, d, J=2.0 Hz), 7.24-7.31 (1H, m), 7.37-7.46 (3H,m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 54 Synthesis of 2-pentylheptanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ:0.80 (t, J=6.5 Hz, 6H), 1.13-1.24 (m, 12H), 1.37-1.48(m, 2H), 1.54-1.66 (m, 2H), 1.71-1.81 (m, 2H), 1.85-1.95 (m, 2H),2.33-2.43 (m, 1H), 2.54 (t, J=7.4 Hz, 2H), 2.64-2.79 (m, 4H), 3.13-3.26(m, 4H), 4.07 (t, J=6.2 Hz, 211), 6.36 (brs, 2H), 6.52 (d, J=9.5 Hz,1H), 6.83 (dd, J=2.1, 8.6 Hz, 1H), 6.87-6.93 (m, 2H), 7.27 (dd, J=7.8,7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Example 55 Synthesis of N-ethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.14 (3H, t, J=7.0 Hz), 1.72-1.82 (2H, m), 1.85-1.95(2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.78 (4H, m), 3.13-3.30 (6H, m),4.12 (2H, t, J=6.0 Hz), 4.80-4.89 (1H, m), 6.33 (2H, s), 6.51 (1H, d,J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.87-6.92 (1H, m),7.13-7.17 (1H, m), 7.24-7.30 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d,J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 56 Synthesis of N,N-dimethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.72-1.82 (2H, m), 1.86-1.95 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.67-2.78 (4H, m), 2.86 (3H, s), 2.96 (3H, s), 3.15-3.24 (4H,m), 4.10 (2H, t, J=6.0 Hz), 6.35 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83(1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.12 (1H, d, J=2.0Hz), 7.24-7.31 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62(1H, d, J=9.5 Hz)

Example 57 Synthesis of N,N-diethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.01 (3H, t, J=7.0 Hz), 1.15 (3H, t, J=7.0 Hz),1.72-1.82 (2H, m), 1.84-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.64-2.808(4H, m), 3.11-3.26 (6H, m), 3.34 (2H, q, J=7.0 Hz), 4.09 (2H, t, J=6.0Hz), 6.36 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5Hz), 6.87-6.92 (1H, m), 7.09 (1H, d, J=2.0 Hz), 7.24-7.31 (1H, m),7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 58 Synthesis of hexanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ:0.85 (t, J=6.8 Hz, 3H), 1.25-1.33 (m, 4H), 1.58-1.69(m, 2H), 1.70-1.85 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.54 (t, J=7.4 Hz, 2H), 2.67-2.78 (m, 4H), 3.15-3.25 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2,8.6 Hz, 1H), 6.84-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43(m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.5Hz, 1H)

Example 59 Synthesis of decanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1) and inthe same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ:0.86 (t, J=6.8 Hz, 3H), 1.17-1.32 (m, 12H), 1.57-1.68(m, 2H), 1.72-1.82 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.54 (t, J=7.5 Hz, 2H), 2.65-2.78 (m, 4H), 3.13-3.25 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (d, J=2.2,8.6 Hz, 1H), 6.86-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43(m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5Hz, 1H)

Example 60 Synthesis of octadecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ:0.88 (t, J=6.8 Hz, 3H), 1.18-1.33 (m, 28H), 1.58-1.67(m, 2H), 1.72-1.82 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.54 (t, J=7.5 Hz, 2H), 2.66-2.79 (m, 4H), 3.14-3.25 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2,8.6 Hz, 1H), 6.87-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43(m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5Hz, 1H)

Example 61 Synthesis of acetic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Acetic acid 7-(4-chlorobutoxy)-2-oxo-2H-quinolin-1-ylmethyl ester (299mg), 1-benzo[b]thiophen-4-ylpiperazine hydrochloride (235 mg), potassiumcarbonate (319 mg) and sodium iodide (152 mg) were suspended in DMF (5ml), and this was stirred at 70° C. for 3 hr and further at 80° C. for 4hr. After cooling to room temperature, to the reaction mixture was addedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate, dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by moderate-pressure silica gelcolumn chromatography (hexane:ethyl acetate=1:0 to 1:9) and further bybasic silica gel column chromatography, and concentrated under reducedpressure to give the title compound (132 mg) as a colorless amorphoussolid.

¹H-NMR (CDCl₃) δ: 1.73-1.83 (m, 2H), 1.84-1.95 (m, 2H), 2.13 (s, 3H),2.54 (t, J=7.4 Hz, 2H), 2.68-2.77 (m, 4H), 3.15-3.24 (m, 4H), 4.09 (t,J=6.3 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.85 (dd, J=2.2,8.6 Hz, 1H), 6.87-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43(m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.63 (d, J=9.5Hz, 1H)

Example 62 Synthesis of N-benzylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized inthe same manner as in Example 7 and in the same manner as in Example 9,the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.80 (2H, m), 1.82-1.92 (2H, m), 2.52 (2H, t,J=7.5 Hz), 2.64-2.77 (4H, m), 3.11-3.24 (4H, m), 4.07 (2H, t, J=6.0 Hz),4.41 (2H, t, J=6.0 Hz), 5.26 (1H, t, J=6.0 Hz), 6.37 (2H, s), 6.51 (1H,d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.88 (1H, d, J=7.0 Hz),7.15 (1H, d, J=1.5 Hz), 7.23-7.34 (6H, m), 7.38 (1H, d, J=5.5 Hz), 7.41(1H, d, J=5.5 Hz), 7.43 (1H, J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.61(1H, d, J=9.5 Hz)

Example 63

s Synthesis of N-cyclohexylmethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized inthe same manner as in Example 7 and in the same manner as in Example 9,the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.83-0.97 (2H, m), 1.02-1.28 (3H, m), 1.36-1.50 (1H,m), 1.54-1.84 (7H, m), 1.86-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz),2.65-2.81 (4H, m), 3.05 (2H, t, J=6.5 Hz), 3.13-3.27 (4H, m), 4.11 (2H,t, J=6.0 Hz), 4.90 (1H, t, J=6.0 Hz), 6.33 (2H, s), 6.51 (1H, d, J=9.5Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.16(1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.45 (3H, m), 7.55 (1H, d,J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 64 Synthesis of{7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethoxycarbonylamino}aceticacid methyl ester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.73-1.84 (2H, m), 1.86-1.94 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.66-2.81 (4H, m), 3.12-3.27 (4H, m), 3.74 (3H, s), 4.00 (2H,d, J=5.5 Hz), 4.11 (2H, t, J=6.0 Hz), 5.34-5.44 (1H, m), 6.36 (2H, s),6.51 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.87-6.92(1H, m), 7.09 (1H, d, J=2.0 Hz), 7.25-7.30 (1H, m), 7.37-7.46 (3H, m),7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 65 Synthesis of tetradecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 61, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (t, J=6.8 Hz, 3H), 1.18-1.33 (m, 20H), 1.58-1.68(m, 2H), 1.72-1.82 (m, 2H), 1.84-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.54 (t, J=7.5 Hz, 2H), 2.66-2.79 (m, 4H), 3.13-3.25 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2,8.6 Hz, 1H), 6.87-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43(m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.5Hz, 1H)

Example 66 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-(2,2,2-trifluoroethoxymethyl)-3,4-dihydro-1H-quinolin-2-one

2,2,2-Trifluoroethanol (0.10 ml) was dissolved in anhydrous THF (3 ml)under a nitrogen atmosphere and sodium hydride (about 55% oil) (60 mg)was added under ice-cooling. The reaction mixture was stirred at roomtemperature for 30 min under a nitrogen atmosphere. The obtainedsolution was ice-cooled again and, under a nitrogen atmosphere, asolution (3 ml) of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester (0.25 g) obtained in Example 5 in anhydrous THF wasadded using a cannula. The reaction mixture was stirred at roomtemperature for 18 hr under a nitrogen atmosphere. To the reactionmixture was added ice water to discontinue the reaction, and the mixturewas extracted with ethyl acetate. The organic layer was dried oversodium sulfate, and concentrated by filtration. The obtained residue waspurified by silica gel column chromatography (ethyl acetate) to give thetitle compound (90 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.69-1.93 (4H, m), 2.47-2.56 (2H, m), 2.64-2.76 (6H,m), 2.80-2.87 (2H, m), 3.13-3.25 (4H, m), 3.93-4.14 (4H, m), 5.42 (2H,s), 6.61 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.86-6.91 (2H, m), 7.05 (1H, d,J=8.5 Hz), 7.24-7.28 (1H, m), 7.37 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5Hz), 7.54 (1H, d, J=8.0 Hz)

Example 67 Synthesis of morpholine-4-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized inthe same manner as in Example 7 and in the same manner as in Example 9,the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.72-1.82 (2H, m), 1.87-1.96 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.66-2.80 (4H, m), 3.16-3.34 (4H, m), 3.37-3.73 (8H, m), 4.10(2H, d, J=6.0 Hz), 6.37 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.84 (1H, dd,J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.09 (1H, d, J=2.5 Hz),7.24-7.30 (1H, m), 7.37-7.43 (2H, m), 7.45 (1H, d, J=8.5 Hz), 7.55 (1H,d, J=8.0 Hz), 7.63 (1H, d, J=9.5 Hz)

Example 68 Synthesis of decanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (t, J=6.8 Hz, 3H), 1.20-1.34 (m, 12H), 1.58-1.68(m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.6 Hz, 2H),2.52 (t, J=7.5 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.13-3.24(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz,1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz,1H)

Example 69 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylbenzyloxycarbamate

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.67-1.79 (2H, m), 1.81-1.92 (2H, m), 2.49 (2H, t,J=7.5 Hz), 2.60-2.74 (4H, m), 3.07-3.21 (4H, m), 4.05 (2H, d, J=6.0 Hz),4.85 (2H, s), 6.37 (2H, s), 6.46 (1H, d, J=9.5 Hz), 6.80-6.88 (2H, m),7.03 (1H, d, J=2.0 Hz), 7.23-7.45 (9H, m), 7.54 (1H, d, J=8.0 Hz), 7.58(1H, d, J=9.5 Hz), 8.11 (1H, s)

Example 70 Synthesis of hexanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 11, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=6.9 Hz, 3H), 1.26-1.34 (m, 4H), 1.59-1.69(m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.53 (t, J=7.4 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.89 (m, 2H), 3.14-3.24(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.88-6.92 (m, 1H), 7.07 (d, J=8.1 Hz,1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz,1H)

Example 71 Synthesis of N-cyclohexylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.02-1.22 (3H, m), 1.24-1.41 (2H, m), 1.52-1.97 (9H,m), 2.54 (2H, t, J=7.5 Hz), 2.64-2.82 (4H, m), 3.11-3.28 (4H, m),3.45-3.59 (1H, m), 4.11 (2H, t, J=6.0 Hz), 4.83 (1H, d, J=8.0 Hz), 6.31(2H, s), 6.50 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89(1H, d, J=7.5 Hz), 7.14 (1H, brs), 7.24-7.30 (1H, m), 7.36-7.45 (3H, m),7.55 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=9.5 Hz)

Example 72 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester methyl ester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.68-1.80 (2H, m), 1.80-1.90 (2H, m), 2.52 (2H, t,J=7.4 Hz), 2.64-2.78 (6H, m), 2.86 (2H, t, J=7.0 Hz), 3.14-3.24 (4H,br), 3.83 (3H, s), 4.00 (2H, t, J=6.2 Hz), 5.95 (2H, brs), 6.59 (1H, dd,J=2.4, 8.2 Hz), 6.69 (1H, d, J=2.2 Hz), 6.90 (1H, d, J=7.4 Hz), 7.06(1H, d, J=8.2 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H,d, J=8.0 Hz)

Example 73 Synthesis of({7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethoxycarbonyl}methylamino)aceticacid methyl ester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.72-1.83 (2H, m), 1.85-1.97 (2H, m), 2.50-2.60 (2H,m), 2.66-2.81 (4H, m), {2.92 (s), 3.02 (s) total 3H (1:1)}, 3.14-3.27(4H, m), {3.53 (s), 3.74 (s) total 3H (1:1)}, 3.91 (1H, s), 4.06 (1H,s), 4.07-4.17 (2H, m), 6.33 (1H, s), 6.38 (1H, s), {6.50 (d, J=9.5 Hz),6.52 (d, J=9.5 Hz total 1H (1:1)}, 6.80-6.86 (1H, m), {6.88 (brs), 6.90(brs) total 1H (1:1)}, {6.98 (d, J=2.0 Hz), 7.06 (d, J=2.0 Hz) total 1H(1:1)}, 7.24-7.30 (1H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz),{7.61 (d, J=9.5 Hz), 7.63 (d, J=9.0 Hz) total 1H (1:1)}

Example 74 Synthesis of undec-10-enoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 61, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.19-1.38 (m, 10H), 1.58-1.67 (m, 2H), 1.72-1.82 (m,2H), 1.86-1.95 (m, 2H), 1.97-2.06 (m, 2H), 2.36 (t, J=7.5 Hz, 2H), 2.54(t, J=7.5 Hz, 2H), 2.66-2.79 (m, 4H), 3.15-3.24 (m, 4H), 4.08 (t, J=6.2Hz, 2H), 4.88-4.94 (m, 1H), 4.94-5.02 (m, 1H), 5.73-5.85 (m, 1H), 6.34(brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H),6.87-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45(d, J=8.6 Hz, ¹H), 7.55 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Example 75 Synthesis of N-octadecylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

In the same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=7.0 Hz), 1.16-1.35 (30H, m), 1.42-1.54(2H, m), 1.70-1.80 (2H, m), 1.81-1.90 (2H, m), 2.52 (2H, t, J=7.5 Hz),2.62-2.78 (6H, m), 2.81-2.90 (2H, m), 3.12-3.27 (6H, m), 4.00 (2H, t,J=6.0 Hz), 4.79 (1H, t, J=5.5 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.5 Hz,8.0 Hz), 6.80 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.05 (1H, d,J=8.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5Hz), 7.55 (1H, d, J=8.0 Hz)

Example 76 Synthesis of N-pentadecylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=7.0 Hz), 1.16-1.35 (24H, m), 1.43-1.53(2H, m), 1.69-1.80 (2H, m), 1.81-1.90 (2H, m), 2.53 (2H, t, J=7.5 Hz),2.63-2.77 (6H, m), 2.81-2.90 (2H, m), 3.14-3.25 (6H, m), 4.00 (2H, t,J=6.0 Hz), 4.80 (1H, t, J=5.5 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.5 Hz,8.0 Hz), 6.80 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.05 (1H, d,J=8.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, dd,J=0.5 Hz, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 77 Synthesis of 2-methylbutyric acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.91 (t, J=7.4 Hz, 3H), 1.17 (d, J=7.0 Hz, 3H),1.42-1.55 (m, 1H), 1.64-1.92 (m, 5H), 2.43 (m, 1H), 2.52 (t, J=7.5 Hz,2H), 2.64-2.79 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25 (m, 4H), 3.98 (t,J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.63 (m, 2H), 6.90 (d, J=7.4 Hz,1H), 7.07 (d, J=8.3 Hz, 1H), 7.27 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.37-7.43(m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 78 Synthesis of 2-methylhexanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.86 (t, J=6.9 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H),1.23-1.32 (m, 4H), 1.36-1.48 (m, 1H), 1.58-1.79 (m, 3H), 1.79-1.89 (m,2H), 2.43-2.56 (m, 3H), 2.64-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.62 (m, 2H), 6.90(d, J=7.5 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H),7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H)

Example 79 Synthesis of N-methyl-N-octadecylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=7.0 Hz), 1.10-1.34 (30H, m), 1.38-1.57(2H, m), 1.68-1.90 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.63-2.79 (6H, m),2.81-2.95 (5H, m), 3.13-3.31 (6H, m), 3.99 (2H, t, J=5.5 Hz), 5.93 (2H,s), 6.59 (1H, d, J=8.0 Hz), 6.77 (1H, d, J=8.0 Hz), 6.89 (1H, d, J=7.5Hz), 7.06 (1H, d, J=8.0 Hz), 7.24-7.31 (1H, m), 7.36-7.43 (2H, m), 7.55(1H, d, J=8.0 Hz)

Example 80 Synthesis of N-benzylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.89 (4H, m), 2.51 (2H, t, J=7.5 Hz), 2.63-2.77(6H, m), 2.86 (2H, t, J=7.5 Hz), 3.13-3.25 (4H, m), 3.98 (2H, t, J=6.0Hz), 4.40 (2H, t, J=6.0 Hz), 5.10-5.18 (1H, m), 5.97 (2H, s), 6.59 (1H,dd, J=2.5 Hz, J=8.5 Hz), 6.80 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz),7.06 (1H, d, J=8.5 Hz), 7.23-7.35 (6H, m), 7.37-7.43 (2H, m), 7.55 (1H,d, J=8.0 Hz)

Example 81 Synthesis of 2-methylpentanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=7.2 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H),1.28-1.46 (m, 3H), 1.61-1.68 (m, 1H), 1.68-1.79 (m, 2H), 1.79-1.90 (m,2H), 2.45-2.56 (m, 3H), 2.64-2.78 (m, 6H), 2.82-2.90 (m, 2H), 3.12-3.25(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.56-6.62 (m, 2H), 6.90(d, J=7.6 Hz, 1H), 7.04-7.10 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.38(d, J s=5.5 Hz, 1H), 7.41 (d, J=5.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H)

Example 82 Synthesis of tetradecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (t, J=6.8 Hz, 3H), 1.20-1.33 (m, 20H), 1.57-1.68(m, 2H), 1.69-1.79 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.6 Hz, 2H),2.52 (t, J=7.5 Hz, 2H), 2.65-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.24(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.60 (dd, J=2.2, 8.1Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 7.07 (d, J=8.1Hz, 1H), 7.24-7.30 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz,1H), 7.55 (d, J=8.0 Hz, 1H)

Example 83 Synthesis of N-cyclohexylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.05-1.21 (4H, m), 1.25-1.43 (2H, m), 1.63-1.93 (8H,m), 2.52 (2H, t, J=7.5 Hz), 2.63-2.78 (6H, m), 2.81-2.90 (2H, m),3.14-3.26 (4H, m), 3.46-3.58 (1H, m), 4.00 (2H, t, J=6.0 Hz), 4.71 (1H,d, J=8.0 Hz), 5.91 (2H, s), 6.59 (1H, dd, J=2.0 Hz, J=8.0 Hz), 6.79 (1H,d, J=2.0 Hz), 6.90 (1H, dd, J=0.5 Hz, J=7.5 Hz), 7.05 (1H, d, J=8.0 Hz),7.24-7.31 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, dd, J=0.5 Hz, J=5.5Hz), 7.55 (1H, d, J=8.0 Hz)

Example 84 Synthesis of 2,2-dimethylhexanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.84 (t, J=6.9 Hz, 3H), 1.14-1.29 (m, 4H), 1.17 (s,6H), 1.47-1.54 (m, 2H), 1.68-1.78 (m, 2H), 1.79-1.89 (m, 2H), 2.52 (t,J=7.5 Hz, 2H), 2.65-2.76 (m, 6H), 2.83-2.89 (m, 2H), 3.15-3.23 (m, 4H),3.97 (d, J=6.3 Hz, 2H), 5.91 (brs, 2H), 6.57-6.62 (m, 2H), 6.88-6.92 (m,1H), 7.07 (d, J=8.2 Hz, 1H), 7.27 (dd, J=7.8 Hz, 7.8 Hz, 1H), 7.37-7.43(m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 85 Synthesis of acetic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.64-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.12 (s, 3H),2.53 (t, J=7.3 Hz, 2H), 2.65-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.13-3.24(m, 4H), 3.99 (t, J=6.2 Hz, 2H), 5.91 (brs, 2H), 6.60 (dd, J=2.3, 8.2Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 7.07 (d, J=8.2Hz, 1H), 7.24-7.30 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz,1H), 7.55 (d, J=8.0 Hz, 1H)

Example 86 Synthesis of morpholine-4-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.79 (2H, m), 1.81-1.90 (2H, m), 2.53 (2H, t,J=7.5 Hz), 2.64-2.78 (6H, m), 2.83-2.90 (2H, m), 3.13-3.25 (4H, m),3.38-3.55 (4H, m), 3.56-3.74 (4H, m), 4.00 (2H, t, J=6.5 Hz), 5.94 (2H,s), 6.60 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.74 (1H, d, J=2.5 Hz), 6.90 (1H,d, J=7.5 Hz), 7.07 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.39 (1H, d,J=5.5 Hz), 7.41 (1H, dd, J=0.5 Hz, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 87 Synthesis of 2-methylbutyric acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.89 (t, J=7.5 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H),1.42-1.54 (m, 1H), 1.60-1.81 (m, 3H), 1.85-1.95 (m, 2H), 2.44 (dt,J=7.0, 7.0 Hz, 1H), 2.54 (t, J=7.5 Hz, 2H), 2.64-2.79 (m, 4H), 3.15-3.25(m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H),6.81-6.87 (m, 2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H),7.37-7.43 (m, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.63(d, J=9.5 Hz, 1H)

Example 88 Synthesis of 2-methylhexanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.81 (t, J=7.0 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H),1.18-1.29 (m, 4H), 1.35-1.47 (m, 1H), 1.59-1.81 (m, 3H), 1.85-1.94 (m,2H), 2.44-2.58 (m, 3H), 2.65-2.80 (m, 4H), 3.13-3.25 (m, 4H), 4.07 (t,J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.81-6.87 (m,2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 2H),7.45 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Example 89 Synthesis of{7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethoxycarbonylamino}aceticacid methyl ester

In the same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.70-1.79 (2H, m), 1.81-1.90 (2H, m), 2.53 (2H, t,J=7.5 Hz), 2.64-2.77 (6H, m), 2.82-2.89 (2H, m), 3.14-3.24 (4H, m), 3.75(3H, s), 3.97-4.05 (4H, m), 4.34 (1H, t, J=5.0 Hz), 5.95 (2H, s), 6.60(1H, dd, J=2.0 Hz, J=8.5 Hz), 6.77 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5Hz), 7.06 (1H, d, J=8.5 Hz), 7.24-7.31 (1H, m), 7.38 (1H, d, J=5.5 Hz),7.41 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 90 Synthesis of({7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethoxycarbonyl}methylamino)aceticacid methyl ester

In the same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.70-1.79 (2H, m), 1.81-1.91 (2H, m), 2.49-2.57 (2H,m), 2.63-2.78 (6H, m), 2.81-2.90 (2H, m), {3.64 (s), 3.75 (s) total 3H(1:1)}, 3.14-3.25 (4H, m), {3.64 (s), 3.75 (s) total 3H (1:1)}, 3.93 (s,1H), 3.97-4.04 (2H, m), 4.06 (1H, s), 5.91 (1H, s), 5.96 (1H, s),6.56-6.63 (1H, m), {6.68 (d, J=2.0 Hz), 6.77 (d, J=2.0 Hz) total 1H(1:1)}, 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, dd, J=8.0 Hz, J=8.0 Hz),7.24-7.31 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55(1H, d, J=8.0 Hz)

Example 91 Synthesis of pentadecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (t, J=6.8 Hz, 3H), 1.17-1.35 (m, 22H), 1.55-1.68(m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.36 (t, J=7.6 Hz, 2H),2.52 (t, J=7.5 Hz, 2H), 2.64-2.76 (m, 6H), 2.83-2.89 (m, 2H), 3.13-3.24(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.59 (dd, J=2.3, 8.2Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.87-6.92 (m, LH), 7.07 (d, J=8.2 Hz,1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz,1H)

Example 92 Synthesis of 2-methylheptanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.85 (t, J=6.8 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H),1.19-1.34 (m, 6H), 1.34-1.47 (m, 1H), 1.60-1.79 (m, 3H), 1.79-1.90 (m,2H), 2.42-2.56 (m, 3H), 2.64-2.78 (m, 6H), 2.82-2.90 (m, 2H), 3.12-3.26(m, 4H), 3.97 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.62 (m, 2H),6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H),7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 93 Synthesis of N-(3,3,3-trifluoropropyl)carbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.79 (2H, m), 1.80-1.90 (2H, m), 2.29-2.43 (2H,m), 2.52 (2H, t, J=7.5 Hz), 2.61-2.77 (6H, m), 2.79-2.89 (2H, m),3.13-3.26 (4H, m), 3.46 (2H, dt, J=6.5 Hz, J=6.5 Hz), 3.99 (2H, t, J=6.0Hz), 5.20 (1H, t, J=6.0 Hz), 5.92 (2H, s), 6.59 (1H, dd, J=2.0 Hz, J=8.5Hz), 6.74 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=8.5Hz), 7.23-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz),7.54 (1H, d, J=8.0 Hz)

Example 94 Synthesis of 2-methylpentanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.86 (t, J=7.2 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H),1.23-1.45 (m, 3H), 1.59-1.82 (m, 3H), 1.85-1.95 (m, 2H), 2.46-2.58 (m,3H), 2.65-2.79 (m, 4H), 3.14-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.34(brs, 2H), 6.52 (d, J=9.4 Hz, 1H), 6.82-6.87 (m, 2H), 6.90 (d, J=7.6 Hz,1H), 7.25-7.30 (m, 1H), 7.39 (d, J=5.5 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H),7.43-7.47 (m, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)

Example 95 Synthesis of heptadecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (t, J=6.9 Hz, 3H), 1.16-1.35 (m, 26H), 1.57-1.68(m, 2H), 1.68-1.79 (m, 2H), 1.79-1.90 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.52 (d, J=7.4 Hz, 2H), 2.64-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.24(m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs, 2H), 6.57-6.63 (m, 2H),6.87-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H),7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 96 Synthesis of furan-3-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.64-1.77 (m, 2H), 1.78-1.88 (m, 2H), 2.50 (t, J=7.5Hz, 2H), 2.63-2.75 (m, 6H), 2.85-2.92 (m, 2H), 3.12-3.23 (m, 4H), 3.98(t, J=6.2 Hz, 2H), 6.09 (brs, 2H), 6.60 (dd, J=2.3, 8.3 Hz, 1H), 6.71(d, J=2.3 Hz, 1H), 6.74-6.77 (m, 1H), 6.87-6.91 (m, 1H), 7.09 (d, J=8.3Hz, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 3H), 7.55 (d, J=7.9Hz, 1H), 8.01-8.05 (m, 1H)

Example 97 Synthesis of N-(2-methoxyethyl)carbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.91 (4H, m), 2.53 (2H, t, J=7.5 Hz), 2.62-2.78(6H, m), 2.81-2.91 (2H, m), 3.13-3.26 (4H, m), 3.33 (3H, s), 3.35-3.48(4H, m), 4.00 (2H, t, J=6.0 Hz), 5.12-5.21 (1H, m), 5.92 (2H, s), 6.59(1H, dd, J=2.0 Hz, J=8.0 Hz), 6.78 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=7.5Hz), 7.06 (1H, d, J=8.0 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz),7.42 (1H, d, J=5.5 Hz), 7.55 (1H, d, J=8.0 Hz)

Example 98 Synthesis of N-furan-2-yl-N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 5 and inthe same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.90 (4H, m), 2.52 (2H, t, J=7.5 Hz), 2.62-2.77(6H, m), 2.81-2.90 (2H, m), 3.12-3.27 (4H, m), 3.99 (2H, t, J=6.0 Hz),4.39 (2H, d, J=6.0 Hz), 5.11-5.19 (1H, m), 5.95 (2H, s), 6.23 (1H, brs),6.30 (1H, brs), 6.59 (1H, dd, J=2.5 Hz, J=8.0 Hz), 6.77 (1H, d, J=2.5Hz), 6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.0 Hz), 7.24-7.30 (1H, m),7.34 (1H, brs), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.55(1H, d, J=8.0 Hz)

Example 99 Synthesis of3-{7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethoxycarbonylamino}-propionicacid ethyl ester

Using carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester synthesized in the same manner as in Example 7 and inthe same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.0 Hz), 1.73-1.83 (2H, m), 1.86-1.96(2H, m), 2.49-2.59 (4H, m), 2.66-2.80 (4H, m), 3.15-3.27 (4H, m),3.45-3.53 (2H, m), 4.07-4.15 (4H, m), 5.36-5.43 (1H, m), 6.32 (2H, s),6.51 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d,J=7.5 Hz), 7.11 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.46 (3H, m),7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)

Example 100 Synthesis of (2-butoxyethoxy)acetic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.90 (t, J=7.4 Hz, 3H), 1.29-1.40 (m, 2H), 1.50-1.59(m, 2H), 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.53 (t, J=7.4 Hz, 2H),2.64-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.13-3.24 (m, 4H), 3.45 (t, J=7.7Hz, 2H), 3.58-3.63 (m, 2H), 3.71-3.76 (m, 2H), 3.98 (t, J=6.2 Hz, 2H),4.22 (s, 2H), 5.99 (brs, 2H), 6.57-6.62 (m, 2H), 6.87-6.92 (m, 1H), 7.07(d, J=7.8 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.36-7.44 (m, 2H), 7.55(d, J=8.0 Hz, 1H)

Example 101 Synthesis of4-{7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethoxycarbonylamino}butyricacid methyl ester

Using carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester synthesized inthe same manner as in Example 7 and in the same manner as in Example 9,the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.73-1.95 (6H, m), 2.36 (2H, t, J=7.0 Hz), 2.54 (2H,t, J=7.5 Hz), 2.66-2.80 (4H, m), 3.116-3.31 (6H, m), 3.64 (3H, s), 4.11(2H, t, J=6.0 Hz) 6.06 (1H, t, J=6.0 Hz), 6.32 (2H, s), 6.51 (1H, d,J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz),7.12 (1H, d, J=1.5 Hz), 7.24-7.30 (1H, m), 7.36-7.46 (3H, m), 7.55 (1H,d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)

Example 102 Synthesis of 1-methylpiperidine-4-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.58-2.06 (m, 10H), 2.04 (s, 3H), 2.28-2.40 (m, 1H),2.52 (t, J=7.4 Hz, 2H), 2.63-2.82 (m, 8H), 2.82-2.90 (m, 2H), 3.14-3.25(m, 4H), 3.97 (t, J=6.3 Hz, 2H), 5.93 (brs, 2H), 6.56-6.62 (m, 2H),6.88-6.92 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H),7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 103 Synthesis of 2,2-dimethylhexanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.77 (t, J=6.8 Hz, 3H), 1.09-1.20 (m, 10H), 1.42-1.52(m, 2H), 1.68-1.95 (m, 4H), 2.54 (t, J=7.5 Hz, 2H), 2.66-2.78 (m, 4H),3.14-3.25 (m, 4H), 4.07 (t, J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d,J=9.5 Hz, 1H), 6.81-6.86 (m, 2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=7.8,7.8 Hz, 1H), 7.36-7.37 (m, 3H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5Hz, 1H)

Example 104 Synthesis of pentadecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (t, J=6.8 Hz, 3H), 1.16-1.34 (m, 22H), 1.57-1.67(m, 2H), 1.67-1.82 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.54 (t, J=7.5 Hz, 2H), 2.65-2.79 (m, 4H), 3.13-3.25 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2,8.6 Hz, 1H), 6.86-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43(m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.5Hz, 1H)

Example 105 Synthesis of 4-methylpentanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.89 (d, J=6.3 Hz, 6H), 1.51-1.63 (m, 3H), 1.69-1.80(m, 2H), 1.80-1.90 (m, 2H), 2.33-2.40 (m, 2H), 2.52 (t, J=7.4 Hz, 2H),2.65-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.24 (m, 4H), 3.99 (t, J=6.2Hz, 2H), 5.91 (brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H), 7.07 (d,J=8.0 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d,J=8.1 Hz, 1H)

Example 106 Synthesis of cycloheptanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.40-1.59 (m, 6H), 1.64-1.79 (m, 6H), 1.80-1.90 (m,2H), 1.90-1.99 (m, 2H), 2.48-2.59 (m, 3H), 2.64-2.78 (m, 6H), 2.82-2.90(m, 2H), 3.14-3.23 (m, 4H), 3.98 (t, J=6.2 Hz, 2H), 5.91 (brs, 2H),6.57-6.63 (m, 2H), 6.90 (d, J=7.3 Hz, 1H), 7.05-7.09 (m, 1H), 7.27 (dd,J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0 Hz, 1H)

Example 107 Synthesis of benzyloxycarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 9, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.67-1.89 (4H, m), 2.51 (2H, t, J=7.5 Hz), 2.61-2.76(6H, m), 2.81-2.90 (2H, m), 3.10-3.23 (4H, m), 4.00 (2H, t, J=6.0 Hz),4.87 (2H, s), 6.00 (2H, s), 6.60 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.73 (1H,d, J=2.5 Hz), 6.86-6.91 (1H, m), 7.07 (1H, d, J=8.5 Hz), 7.24-7.42 (8H,m), 7.55 (1H, d, J=8.0 Hz), 7.59 (1H, brs)

Example 108 Synthesis of heptadecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (t, J=6.9 Hz, 3H), 1.17-1.33 (m, 26H), 1.57-1.67(m, 2H), 1.69-1.82 (m, 2H), 1.85-1.95 (m, 2H), 2.36 (t, J=7.5 Hz, 2H),2.54 (t, J=7.5 Hz, 2H), 2.67-2.77 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2,8.6 Hz, 1H), 6.86-6.91 (m, 2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.36-7.43(m, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5Hz, 1H)

Example 109 Synthesis of N-(2-methoxyethyl)carbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.73-1.83 (2H, m), 1.86-1.96 (2H, m), 2.55 (2H, t,J=7.5 Hz), 2.67-2.80 (4H, m), 3.16-3.25 (4H, m), 3.32 (3H, s), 3.36-3.47(4H, m), 4.11 (2H, d, J=6.0 Hz), 5.17-5.24 (1H, m), 6.33 (2H, s), 6.51(1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5Hz), 7.13 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.47 (3H, m), 7.55(1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 110 Synthesis of N-furan-2-yl-N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.71-1.82 (2H, m), 1.83-1.96 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.65-2.80 (4H, m), 3.13-3.28 (4H, m), 4.10 (2H, t, J=6.0 Hz),4.39 (2H, d, J=6.0 Hz), 5.19-5.29 (1H, m), 6.21 (1H, d, J=3.0 Hz), 6.30(1H, d, J=3.0 Hz), 6.36 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.83 (1H, dd,J=2.0 Hz, J=8.5 Hz), 6.87-6.91 (1H, m), 7.12 (1H, d, J=1.5 Hz),7.24-7.30 (1H, m), 7.33 (1H, brs), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0Hz), 7.61 (1H, d, J=9.5 Hz)

Example 111 Synthesis of N-benzyl-N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.79 (2H, m), 1.82-1.92 (2H, m), 2.53 (2H, t,J=7.0 Hz), 2.64-2.76 (4H, m), {2.80 (s), 2.93 (s) total 3H (1:1)},3.13-3.25 (4H, m), 4.02 (1H, t, J=6.0 Hz), 4.08 (1H, t, J=6.0 Hz), 4.37(1H, s), 4.52 (1H, s), 6.41 (1H, s), 6.43 (1H, s), 6.52 (1H, dd, J=8.5Hz, J=8.5 Hz), 6.80-6.91 (2H, m), {6.99-7.09 (m), 7.14-7.19 (m) total 3H(1:1)}, 7.21-7.35 (4H, m), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz),7.62 (1H, dd, J=9.0 Hz, J=9.0 Hz)

Example 112 Synthesis of N-allylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.73-1.83 (2H, m), 1.85-1.96 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.64-2.80 (4H, m), 3.13-3.26 (4H, m), 3.84 (2H, t, J=5.5 Hz),4.11 (2H, t, J=6.0 Hz), 4.91-5.01 (1H, m), 5.08-5.24 (2H, m), 5.77-5.90(1H, m), 6.35 (2H, s), 6.51 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz,J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.14 (1H, brs), 7.24-7.30 (1H, m),7.37-7.47 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 113 Synthesis of N-pyridin-2-yl-N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.64-1.81 (2H, m), 1.83-1.93 (2H, m), 2.53 (2H, t,J=7.5 Hz), 2.66-2.80 (4H, m), 3.12-3.25 (4H, m), 4.08 (2H, t, J=6.0 Hz),4.53 (2H, d, J=5.0 Hz), 6.01 (1H, t, J=5.0 Hz), 6.38 (2H, s), 6.52 (1H,d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.88 (1H, d, J=7.5 Hz),7.03-7.19 (2H, m), 7.21-7.30 (2H, m), 7.36-7.46 (3H, m), 7.55 (1H, d,J=8.0 Hz), 7.59-7.67 (2H, m), 8.40-8.57 (1H, m)

Example 114 Synthesis of undec-10-enoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.21-1.40 (m, 10H), 1.54-1.68 (m, 2H), 1.68-1.79 (m,2H), 1.79-1.90 (m, 2H), 1.97-2.06 (m, 2H), 2.36 (t, J=9.5 Hz, 2H), 2.52(t, J=7.4 Hz, 2H), 2.64-2.76 (m, 6H), 2.83-2.96 (m, 2H), 3.14-3.23 (m,4H), 3.99 (t, J=6.3 Hz, 2H), 4.89-4.94 (m, 1H), 4.94-5.02 (m, 1H),5.73-5.86 (m, 1H), 5.92 (brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H),7.07 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.36-7.43 (m, 2H),7.55 (d, J=7.9 Hz, 1H)

Example 115 Synthesis of furan-3-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.67-1.81 (m, 2H), 1.81-1.97 (m, 2H), 2.52 (dd, J=7.5Hz, 2H), 2.62-2.78 (m, 4H), 3.11-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H),6.51 (brs, 2H), 6.54 (d, J=9.5 Hz, 1H), 6.74-6.77 (m, 1H), 6.84 (dd,J=2.2, 8.6 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.96 (d, J=2.2 Hz, 1H), 7.27(dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 3H), 7.46 (d, J=8.6 Hz, 1H), 7.55(d, J=8.0 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H), 8.01-8.04 (m, 1H)

Example 116 Synthesis of N-phenethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.71-1.82 (2H, m), 1.85-1.96 (2H, m), 2.53 (2H, t,J=7.5 Hz), 2.63-2.77 (4H, m), 2.81 (2H, t, J=7.0 Hz), 3.13-3.26 (4H, m),3.44-3.52 (2H, m), 4.11 (2H, t, J=6.0 Hz), 4.90 (1H, t, J=5.5 Hz), 6.32(2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.88(1H, d, J=7.5 Hz), 7.12-7.34 (7H, m), 7.37-7.47 (3H, m), 7.55 (1H, d,J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)

Example 117 Synthesis of N-isopropyl-carbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.15 (6H, d, J=6.5 Hz), 1.72-1.82 (2H, m), 1.85-1.94(2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.78 (4H, m), 3.12-3.26 (4H, m),3.78-3.90 (1H, m), 4.10 (2H, d, J=6.0 Hz), 4.93 (1H, d, J=7.5 Hz), 6.29(2H, s), 6.48 (1H, d, J=9.5 Hz), 6.82 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.88(1H, d, J=7.5 Hz), 7.13 (1H, brs), 7.26 (1H, dd, J=8.0 Hz, J=8.0 Hz),7.35-7.44 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=9.5 Hz)

Example 118 Synthesis of 2-methylheptanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.81 (d, J=6.8 Hz, 3H), 1.15 (d, J=7.0 Hz, 3H),1.17-1.30 (m, 6H), 1.35-1.46 (m, 1H), 1.58-1.71 (m, 1H), 1.71-1.82 (m,2H), 1.82-1.98 (m, 2H), 2.43-2.58 (m, 3H), 2.66-2.79 (m, 4H), 3.14-3.25(m, 4H), 4.07 (d, J=6.2 Hz, 2H), 6.35 (brs, 2H), 6.52 (d, J=9.5 Hz, LH),6.84 (dd, J=2.2, 8.5 Hz, 1H), 6.85-6.92 (m, 2H), 7.27 (dd, J=7.9, 7.9Hz, 1H), 7.37-7.43 (m, 2H), 7.44 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.0 Hz,1H), 7.62 (d, J=9.5 Hz, 1H)

Example 119 Synthesis of cycloheptanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.37-1.58 (m, 6H), 1.62-1.81 (m, 6H), 1.84-1.97 (m,4H), 2.50-2.58 (m, 3H), 2.67-2.79 (m, 4H), 3.15-3.25 (m, 4H), 4.07 (t,J=6.2 Hz, 2H), 6.33 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.82-6.86 (m,2H), 6.87-6.92 (m, 1H), 7.27 (dd, J=8.0, 8.0 Hz, 1H), 7.37-7.43 (m, 2H),7.43-7.47 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H)

Example 120 Synthesis of tetrahydropyran-4-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.90 (m, 8H), 2.52 (t, J=7.4 Hz, 2H), 2.56-2.65(m, 1H), 2.65-2.77 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25 (m, 4H),3.37-3.45 (m, 2H), 3.90-4.01 (m, 4H), 5.94 (brs, 2H), 6.57 (d, J=2.2 Hz,1H), 6.60 (d, J=2.2, 8.2 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 7.07 (d, J=8.2Hz, 1H), 7.24-7.30 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.42 d, J=5.6 Hz,1H), 7.55 (d, J=8.0 Hz, 1H)

Example 121 Synthesis of malonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester tert-butyl ester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.44 (s, 9H), 1.69-1.80 (m, 2H), 1.80-1.89 (m, 2H),2.52 (d, J=7.4 Hz, 2H), 2.64-2.79 (m, 6H), 2.83-2.90 (m, 2H), 3.14-3.25(m, 4H), 3.35 (s, 2H), 4.01 (t, J=6.2 Hz, 2H), 5.96 (brs, 2H), 6.00 (dd,J=2.3, 8.2 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.90 (d, J=7.4 Hz, 1H), 7.07(d, J=8.2 Hz, 1H), 7.25-7.30 (m, 1H), 7.37-7.43 (m, 2H), 7.55 (d, J=8.0Hz, 1H).

Example 122 Synthesis of N-isobutylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.86-0.93 (6H, m), 1.69-1.82 (3H, m), 1.84-1.94 (2H,m), 2.54 (2H, t, J=7.5 Hz), 2.65-2.78 (4H, m), 3.03 (2H, t, J=6.5 Hz),3.13-3.25 (4H, m), 4.10 (2H, d, J=6.0 Hz), 5.09 (1H, t, J=6.0 Hz), 6.32(2H, s), 6.49 (1H, d, J=9.5 Hz), 6.82 (1H, dd, J=2.0 Hz, J=8.5 Hz),6.86-6.91 (1H, m), 7.13 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.36-7.44(3H, m), 7.54 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=9.5 Hz)

Example 123 Synthesis of 4,4-difluoropiperidine-1-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.72-2.07 (8H, m), 2.54 (2H, t, J=7.5 Hz), 2.64-2.78(4H, m), 3.13-3.25 (4H, m), 3.48-3.71 (4H, m), 4.10 (2H, d, J=6.0 Hz),6.36 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.85 (1H, dd, J=2.0 Hz, J=8.5 Hz),6.89 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=2.0 Hz), 7.27 (1H, dd, J=8.0 Hz,J=8.0 Hz), 7.39 (1H, d, J=5.5 Hz), 7.41 (1H, d, J=5.5 Hz), 7.45 (1H, d,J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=9.5 Hz)

Example 124 Synthesis of 4,4,4-trifluorobutyric acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.43-2.57 (m,4H), 2.62-2.77 (m, 8H), 2.83-2.90 (m, 2H), 3.13-3.24 (m, 4H), 3.99 (t,J=6.2 Hz, 2H), 5.95 (brs, 2H), 6.57-6.63 (m, 2H), 6.87-6.92 (m, 1H),7.08 (d, J=8.1 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.42 (m, 2H),7.55 (d, J=8.1 Hz, 1H)

Example 125 Synthesis of N-furan-2-ylmethyl-N-methylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.82 (2H, m), 1.84-1.94 (2H, m), 2.53 (2H, t,J=7.5 Hz), 2.65-2.78 (4H, m), {2.84 (s), 2.97 (s) total 3H (1:1)},3.13-3.26 (4H, m), 4.05 (1H, d, J=6.0 Hz), 4.10 (1H, t, J=6.0 Hz), 4.31(1H, s), 4.49 (1H, s), {6.02 (d, J=2.5 Hz), 6.24 (d, J=2.5 Hz) total 1H(1:1)}, {6.17 (brs), 6.32 (brs) total 1H (1:1)}, 6.39 (2H, s), 6.52 (1H,d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz),{7.02 (brs), 7.12 (brs) total 1H (1:1)}, {7.19 (brs), 7.36 (brs) total1H (1:1)}, 7.24-7.31 (1H, m), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz),7.62 (1H, d, J=9.5 Hz)

Example 126 Synthesis of 4-methylpentanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (d, J=6.3 Hz, 6H), 1.50-1.62 (m, 3H), 1.70-1.82(m, 2H), 1.86-1.95 (m, 2H), 2.33-2.40 (m, 2H), 2.54 (t, J=7.5 Hz, 2H),2.66-2.79 (m, 4H), 3.14-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H), 6.33 (brs,2H), 6.52 (d, J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.86-6.91 (m,2H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.45 (d, J=8.6 Hz,1H), 7.55 (d, J=8.0 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)

Example 127 Synthesis of cyclobutanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.68-1.79 (m, 2H), 1.80-2.03 (m, 4H), 2.15-2.25 (m,2H), 2.25-2.37 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 2.64-2.77 (m, 6H),2.83-2.89 (m, 2H), 3.13-3.24 (m, 5H), 3.98 (t, J=6.2 Hz, 2H), 5.92 (brs,2H), 6.57-6.62 (m, 2H), 6.90 (d, J=7.5 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H),7.24-7.30 (m, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.55(d, J=8.1 Hz, 1H)

Example 128 Synthesis of benzofuran-5-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.62-1.74 (m, 2H), 1.75-1.86 (m, 2H), 2.46 (t, J=7.5Hz, 2H), 2.58-2.71 (m, 4H), 2.71-2.79 (m, 2H), 2.82-2.93 (m, 2H),3.07-3.20 (m, 4H), 3.96 (t, J=6.3 Hz, 2H), 6.19 (brs, 2H), 6.61 (dd,J=2.3, 8.3 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H), 6.79-6.83 (m, 1H), 6.85-6.90(m, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.36-7.41(m, 2H), 7.52 (d, J=8.7 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.65 (d, J=2.2Hz, 1H), 8.03 (dd, J=1.7, 8.7 Hz, 1H). 8.36 (d, J=1.7 Hz, 1H)

Example 129 Synthesis of N-methoxycarbamic acid(7-{4-[4-(benzo[b]thiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-2H-quinolin-1-yl)methyl

In the same manner as in Example 10, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.72-1.82 (2H, m), 1.84-1.95 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.65-2.79 (4H, m), 3.13-3.26 (4H, m), {3.51 (s), 3.73 (s)total 3H (1:3)}, 4.07-4.17 (2H, m), {6.33 (s), 6.39 (s) total 2H (1:3)},6.48-6.53 (1H, m), 6.80-6.88 (2H, m), {7.05 (d, J=2.0 Hz), 7.13 (d,J=2.0 Hz) total 1H (3:1)}, 7.24-7.30 (1H, m), 7.37-7.47 (3H, m), 7.55(1H, d, J=8.0 Hz), {7.58 (brs), 7.83 (brs) total 1H (1:3)}, 7.62 (1H, d,J=9.5 Hz)

Example 130 Synthesis of tetrahydropyran-4-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.71-1.95 (m, 8H), 2.54 (t, J=7.5 Hz, 2H), 2.57-2.66(m, 1H), 2.67-2.79 (m, 4H), 3.14-3.25 (m, 4H), 3.34-3.43 (m, 2H), 3.93(dt, J=3.6, 7.6 Hz, 2H), 4.08 (t, J=6.3 Hz, 2H), 6.35 (brs, 2H), 6.52(d, J=9.5 Hz, 1H), 6.81-6.87 (m, 2H), 6.87-6.92 (m, 1H), 7.27 (dd,J=7.9, 7.9 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.46(d, J=8.4 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.63 (d, J=9.5 Hz, 1H)

Example 131 Synthesis of thiophene-2-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.66-1.76 (m, 2H), 1.77-1.89 (m, 2H), 2.50 (t, J=7.5Hz, 2H), 2.62-2.76 (m, 6H), 2.85-2.92 (m, 2H), 3.10-3.23 (m, 4H), 3.98(t, J=6.2 Hz, 2H), 6.14 (brs, 2H), 6.61 (dd, J=2.3, 8.2 Hz, 1H), 6.75(d, J=2.3 Hz, 1H), 6.86-6.91 (m, 1H), 7.05-7.11 (m, 2H), 7.27 (dd,J=7.8, 7.8 Hz, 1H), 7.37-7.43 (m, 2H), 7.53-7.58 (m, 2H), 7.82 (dd,J=1.2, 3.8 Hz, 1H)

Example 132 Synthesis of nicotinic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

In the same manner as in Example 48, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.64-1.76 (m, 2H), 1.77-1.88 (m, 2H), 2.49 (t, J=7.5Hz, 2H), 2.61-2.78 (m, 6H), 2.87-2.94 (m, 2H), 3.10-3.24 (m, 4H), 3.98(t, J=6.3 Hz, 2H), 6.19 (brs, 2H), 6.62 (dd, J=2.3, 8.3 Hz, 1H), 6.72(d, J=2.3 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.27(dd, J=7.8, 7.8 Hz, 1H), 7.35-7.42 (m, 3H), 7.55 (d, J=8.0 Hz, 1H), 8.30(ddd, J=2.0, 2.0, 8.0 Hz, 1H), 8.77 (dd, J=1.7 Hz, 4.9 Hz, 1H),9.21-9.25 (m, 1H)

Example 133 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester 4-nitrophenyl ester

7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one(2.0 g) was suspended in anhydrous THF (40 ml) under a nitrogenatmosphere, and sodium hydride (about 55% oil) (0.22 g) was added. Themixture was refluxed for 30 min under a nitrogen atmosphere. Theobtained solution was cooled to was cooled to −70° C., and a solution(20 ml) of chloromethyl-4-nitrophenyl carbonate (1.50 g) in anhydrousTHF with cannula. The reaction mixture was stirred at room temperaturefor 3 hr. Water was added to the reaction mixture to discontinue thereaction, and the mixture was extracted with ethyl acetate. The organiclayer was dried over sodium sulfate, and concentrated by filtration. Theobtained residue was purified by silica gel column chromatography (ethylacetate) to give the component (Rf value: 0.62, ethyl acetate, 0.67 g)as a pale-yellow amorphous compound. The obtained compound was used forthe next reaction step without further purification.

Example 134 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester dodecyl ester

1-Dodecanol (0.10 g) was dissolved in anhydrous THF (5 ml) under anitrogen atmosphere and sodium hydride (about 55% oil) (25 mg) was addedunder ice-cooling with stirring. The reaction mixture was stirred atroom temperature for 30 min under a nitrogen atmosphere, and then themixture was ice-cooled. To the mixture was added a solution (5 ml) ofcarbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester 4-nitrophenyl ester obtained in Example 133 (0.33 g) in anhydrousTHF using a cannula. Under a nitrogen atmosphere, the reaction mixturewas stirred with ice-cooling for 2 hr, and at room temperature for 1 hr.Water was added to the reaction mixture to discontinue the reaction, andthe mixture was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, and concentrated by filtration. The obtainedresidue was purified by silica gel column chromatography (ethylacetate:hexane 30=1:1) to give the title compound (0.14 g) as acolorless oil.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=7.0 Hz), 1.17-1.38 (18H, m), 1.59-1.70(2H, m), 1.73-1.82 (2H, m), 1.86-1.95 (2H, m), 2.54 (2H, t, J=7.5 Hz),2.69-2.78 (4H, m), 3.16-3.24 (4H, m), 4.10 (2H, t, J=6.0 Hz), 4.18 (2H,t, J=6.5 Hz), 6.35 (2H, brs), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd,J=2.0 Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 6.93 (1H, d, J=2.0 Hz),7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.42 (1H, d, J=5.5 Hz), 7.44(1H, d, J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)

Example 135 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester decyl ester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1), and inthe same manner as in Example 5, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=7.0 Hz), 1.17-1.38 (14H, m), 1.62-1.70(2H, m), 1.72-1.83 (2H, m), 1.86-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz),2.64-2.81 (4H, m), 3.12-3.26 (4H, m), 4.07-4.13 (2H, m), 4.18 (2H, t,J=6.5 Hz), 6.35 (2H, brs), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0Hz, J=8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 6.93 (1H, d, J=2.0 Hz), 7.24-7.30(1H, m), 7.38 (1H, d, J=5.5 Hz), 7.42 (1H, d, J=5.5 Hz), 7.44 (1H, d,J=8.5 Hz), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)

Example 136 Synthesis of cyclobutanecarboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.66-1.84 (m, 2H), 1.84-2.05 (m, 4H), 2.14-2.24 (m,2H), 2.24-2.36 (m, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.65-2.80 (m, 4H),3.12-3.26 (m, 5H), 4.08 (t, J=6.2 Hz, 2H), 6.34 (brs, 2H), 6.52 (d,J=9.5 Hz, 1H), 6.84 (dd, J=2.2, 8.5 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H),6.89 (d, J=7.6 Hz, 1H), 7.24-7.30 (m, 1H), 7.39 (d, J=5.6 Hz, 1H), 7.41(d, J=5.6 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.62(d, J=9.5 Hz, 1H)

Example 137 Synthesis of benzofuran-5-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.66-1.78 (m, 2H), 1.78-1.92 (m, 2H), 2.48 (t, J=7.4Hz, 2H), 2.59-2.74 (m, 4H), 3.10-3.20 (m, 4H), 4.07 (t, J=6.2 Hz, 2H),6.57 (d, J=9.5 Hz, 1H), 6.61 (brs, 2H), 6.76-6.81 (m, 1H), 6.84 (dd,J=2.1, 8.6 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 7.00-7.04 (m, 1H), 7.27 (dd,J=7.9, 7.9 Hz, 1H), 7.37-7.42 (m, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.50 (d,J=8.7 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.62-7.69 (m, 2H), 8.03 (dd,J=1.7, 8.7 Hz, 1H), 8.35 (d, J=1.7 Hz, 1H)

Example 138 Synthesis of 4,4,4-trifluorobutyric acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.68-1.82 (m, 2H), 1.86-1.96 (m, 2H), 2.43-2.58 (m,4H), 2.62-2.69 (m, 2H), 2.69-2.79 (m, 4H), 3.14-3.26 (m, 4H), 4.08 (t,J=6.2 Hz, 2H), 6.36 (brs, 2H), 6.52 (d, J=9.5 Hz, 1H), 6.83-6.88 (m,2H), 6.88-6.92 (m, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.37-7.43 (m, 2H),7.46 (d, J=8.3 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H)

Example 139 Synthesis of N-(3,3,3-trifluoropropyl)carbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 134, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.72-1.95 (4H, m), 2.30-2.44 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.65-2.82 (4H, m), 3.13-3.26 (4H, m), 3.48 (2H, dt, J=6.5 Hz,J=6.5 Hz), 4.04-4.14 (2H, m), 5.32-5.39 (1H, m), 6.31 (2H, s), 6.48 (1H,d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz, J=8.5 Hz), 6.86-6.91 (1H, m), 7.07(1H, d, J=2.0 Hz), 7.24-7.30 (1H, m), 7.37-7.44 (3H, m), 7.54 (1H, d,J=8.0 Hz), 7.58 (1H, d, J=9.5 Hz)

Example 140 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester (E)-3-phenyl-allyl ester

In the same manner as in Example 134, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.80 (2H, m), 1.82-1.94 (2H, m), 2.51 (2H, t,J=7.5 Hz), 2.63-2.77 (4H, m), 3.12-3.24 (4H, m), 4.05-4.11 (2H, m), 4.34(1H, dd, J=1.0 Hz, J=6.5 Hz), 4.83 (1H, dd, J=1.0 Hz, J=6.5 Hz),6.16-6.30 (1H, m), 6.38 (2H, brs), 6.50 (1H, dd, J=2.0 Hz, J=9.5 Hz),6.57-6.70 (1H, m), 6.80-6.85 (1H, m), 6.87 (1H, brd, J=7.5 Hz), 6.93(1H, brs), 7.20-7.46 (9H, m), 7.54 (1H, d, J=8.0 Hz), 7.59 (1H, dd,J=3.5 Hz, J=9.5 Hz)

Example 141 Synthesis of thiophene-2-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.66-1.82 (m, 2H), 1.84-1.93 (m, 2H), 2.52 (t, J=7.5Hz, 2H), 2.64-2.77 (m, 4H), 3.12-3.24 (m, 4H), 4.08 (t, J=6.2 Hz, 2H),6.52-6.60 (m, 3H), 6.84 (dd, J=2.1, 8.6 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H),7.00 (d, J=2.1 Hz, 1H), 7.07 (dd, J=3.8, 4.9 Hz, 1H), 7.27 (dd, J=7.8,7.8 Hz, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.45 (d,J=8.6 Hz, 1H), 7.53-7.59 (m, 2H), 7.64 (d, J=9.5 Hz, 1H), 7.82 (dd,J=1.2, 3.8 Hz, 1H)

Example 142 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester decyl ester

In the same manner as in Example 5, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=7.0 Hz), 1.19-1.41 (14H, m), 1.62-1.80(4H, m), 1.82-1.91 (2H, m), 2.52 (2H, t, J=7.5 Hz), 2.64-2.77 (6H, m),2.82-2.90 (2H, m), 3.14-3.24 (4H, m), 4.00 (2H, t, J=6.0 Hz), 4.17 (2H,t, J=6.5 Hz), 5.94 (2H, s), 6.59 (1H, dd, J=2.5 Hz, J=8.5 Hz), 6.69 (1H,dd, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06 (1H, d, J=8.5 Hz), 7.25-7.30(1H, m), 7.38 (1H, d, J=5.5 Hz), 7.40-7.43 (1H, m), 7.55 (1H, d, J=8.0Hz)

Example 143 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester hexyl ester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=6.9 Hz), 1.20-1.90 (12H, m), 2.52 (2H,t, J=7.4 Hz), 2.60-2.80 (6H, m), 2.83-2.88 (2H, m), 3.20 (4H, br), 4.00(2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.7 Hz), 5.94 (2H, brs), 6.59 (1H, dd,J=2.4, 8.2 Hz), 6.69 (1H, d, J=2.3 Hz), 6.90 (1H, d, J=7.6 Hz), 7.06(1H, d, J=8.3 Hz), 7.20-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d,J=8.0 Hz)

Example 144 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester hexadecyl ester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=6.8 Hz), 1.20-1.90 (32H, m), 2.53 (2H,t, J=7.4 Hz), 2.64-2.78 (6H, m), 2.80-2.90 (2H, m), 3.20 (4H, br), 4.00(2H, t, J=6.2 Hz), 4.17 (2H, t, J=6.8 Hz), 5.94 (2H, brs), 6.59 (1H, dd,J=2.3, 8.3 Hz), 6.69 (1H, d, J=2.3 Hz), 6.89 (1H, d, J=7.6 Hz), 7.06(1H, d, J=8.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.35-7.45 (2H, m), 7.54 (1H,d, J=8.0 Hz)

Example 145 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester heptyl ester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=7.0 Hz), 1.22-1.40 (6H, m), 1.52-1.90(8H, m), 2.53 (2H, t, J=7.4 Hz), 2.64-2.78 (6H, m), 2.86 (2H, t, J=7.2Hz), 3.20 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.17 (2H, t, J=6.8 Hz), 5.94(2H, brs), 6.59 (1H, dd, J=2.4, 8.3 Hz), 6.69 (1H, d, J=2.3 Hz), 6.90(1H, d, J=7.6 Hz), 7.06 (1H, d, J=8.2 Hz), 7.27 (1H, t, J=7.8 Hz),7.35-7.45 (2H, m), 7.55 (1H, d, J=8.1 Hz)

Example 146 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester cyclohexyl ester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-onesynthesized in the same manner as in WO2006/112464 (Example 1), and inthe same manner as in Example 5, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.17-1.28 (1H, m), 1.29-1.41 (2H, m), 1.42-1.57 (3H,m), 1.68-1.82 (4H, m), 1.84-1.98 (4H, m), 2.53 (2H, t, J=7.5 Hz),2.64-2.80 (4H, m), 3.12-3.26 (4H, m), 4.09 (2H, t, J=6.0 Hz), 4.64-4.72(1H, m), 6.34 (2H, s), 6.49 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.0 Hz,8.5 Hz), 6.89 (1H, d, J=7.5 Hz), 6.92 (1H, d, J=2.0 Hz), 7.23-7.30 (1H,m), 7.36-7.44 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.59 (LH, d, J=9.5 Hz)

Example 147 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester 2,2,2-trifluoro-ethyl ester

In the same manner as in Example 5, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.69-1.79 (2H, m), 1.81-1.90 (2H, m), 2.51 (2H, t,J=7.5 Hz), 2.63-2.76 (6H, m), 2.81-2.90 (2H, m), 3.13-3.26 (4H, m), 3.99(2H, t, J=6.0 Hz), 4.55 (2H, q, J=8.0 Hz), 6.00 (2H, s), 6.61 (1H, dd,J=2.5 Hz, 8.0 Hz), 6.65 (1H, d, J=2.5 Hz), 6.86-6.91 (1H, m), 7.07 (1H,d, J=8.5 Hz), 7.23-7.29 (1H, m), 7.37 (1H, d, J=5.5 Hz), 7.39-7.43 (1H,m), 7.54 (1H, d, J=8.0 Hz)

Example 148 Synthesis of malonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester tert-butyl ester

In the same manner as in Example 22, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.38 (s, 9H), 1.69-1.83 (m, 2H), 1.85-1.95 (m, 2H),2.55 (t, J=7.4 Hz, 2H), 2.67-2.79 (m, 4H), 3.14-3.25 (m, 4H), 3.35 (s,2H), 4.13 (t, J=6.1 Hz, 2H), 6.37 (brs, 2H), 6.51 (d, J=9.5 Hz, 1H),6.84 (dd, J=2.2, 8.6 Hz, 1H), 6.87-6.92 (m, 2H), 7.27 (dd, J=7.8, 7.8Hz, 1H), 7.37-7.43 (m, 2H), 7.44 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.0 Hz,1H), 7.63 (d, J=9.5 Hz, 1H)

Example 149 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester octyl ester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=6.8 Hz), 1.20-1.40 (8H, m), 1.60-1.90(8H, m), 2.53 (2H, t, J=7.4 Hz), 2.64-2.78 (6H, m), 2.86 (2H, t, J=6.8Hz), 3.20 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.17 (2H, t, J=6.8 Hz), 5.94(2H, brs), 6.59 (1H, dd, J=2.3, 8.2 Hz), 6.69 (1H, d, J=2.3 Hz), 6.90(1H, d, J=7.6 Hz), 7.06 (1H, d, J=8.1 Hz), 7.27 (1H, t, J=7.8 Hz),7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0 Hz)

Example 150 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester cyclohexyl ester

In the same manner as in Example 5, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.17-1.28 (1H, m), 1.29-1.41 (2H, m), 1.43-1.58 (3H,m), 1.68-1.79 (4H, m), 1.80-1.89 (2H, m), 1.90-1.99 (2H, m), 2.52 (2H,t, J=7.5 Hz), 2.64-2.77 (6H, m), 2.82-2.89 (2H, m), 3.14-3.25 (4H, m),4.00 (2H, t, J=6.0 Hz), 4.62-4.71 (1H, m), 5.94 (2H, s), 6.59 (1H, dd,J=2.5 Hz, 8.5 Hz), 6.69 (1H, d, J=2.5 Hz), 6.90 (1H, d, J=7.5 Hz), 7.06(1H, d, J=8.5 Hz), 7.24-7.30 (1H, m), 7.38 (1H, d, J=5.5 Hz), 7.40-7.44(1H, m), 7.55 (1H, d, J=8.0 Hz)

Example 151 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester butyl ester

In the same manner as in Example 5, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.4 Hz), 1.34-1.46 (2H, m), 1.60-1.90(6H, m), 2.52 (2H, t, J=7.4 Hz), 2.64-2.76 (6H, m), 2.82-2.88 (2H, m),3.16-3.26 (4H, br), 4.00 (2H, t, J=6.2 Hz), 4.19 (2H, t, J=6.7 Hz), 5.94(2H, brs), 6.59 (1H, dd, J=2.3, 8.2 Hz), 6.69 (1H, d, J=2.3 Hz), 6.89(18, d, J=7.6 Hz), 7.06 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=7.8 Hz),7.36-7.44 (2H, m), 7.55 (1H, d, J=8.1 Hz)

Example 152 Synthesis of N-methyl-N-pyridin-2-ylmethylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.68-1.81 (2H, m), 1.82-1.94 (2H, m), 2.47-2.58 (2H,m), 2.64-2.78 (4H, m), {2.91 (s), 3.06 (s) total 3H (1:1)}, 3.13-3.25(4H, m), 4.00-4.10 (2H, m), 4.47 (1H, s), 4.65 (1H, s), 6.37 (1H, brs),6.43 (1H, brs), {6.48 (d, J=9.5 Hz), 6.53 (d, J=9.5 Hz) total 1H (1:1)},6.78-6.97 (2H, m), 6.99-7.05 (1H, m), 7.13-7.21 (1H, m), 7.23-7.31 (2H,m), 7.36-7.47 (3H, m), 7.52-7.68 (3H, m), {8.38 (d, J=4.5 Hz), 8.54 (d,J=4.5 Hz) total 1H (1:1)}

Example 153 Synthesis of thiomorpholine-4-carboxylic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester

In the same manner as in Example 14, the title compound was obtained.

¹H-NMR (CDCl₃) δ: 1.72-1.82 (2H, m), 1.86-1.95 (2H, m), 2.45-2.52 (2H,m), 2.54 (2H, t, J=7.5 Hz), 2.58-2.64 (2H, m), 2.68-2.79 (4H, m),3.15-3.26 (4H, m), 3.63-3.72 (2H, m), 3.73-3.83 (2H, m), 4.10 (2H, d,J=6.5 Hz), 6.36 (2H, s), 6.52 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.0 Hz,J=8.5 Hz), 6.87-6.92 (1H, m), 7.06 (1H, d, J=2.0 Hz), 7.24-7.30 (1H, m),7.37-7.47 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=9.5 Hz)

Example 154 Synthesis of dodecanoic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

Using7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-oneobtained in Reference Example 18, the title compound was synthesized inthe same manner as in Example 5.

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=6.9 Hz), 1.20-1.32 (22H, m), 1.56-1.68(2H, m), 1.68-1.80 (2H, m), 1.80-1.90 (2H, m), 2.35 (2H, t, J=7.5 Hz),2.50-2.56 (4H, m), 2.68-2.76 (4H, m), 3.14-3.24 (4H, m), 3.99 (2H, t,J=6.2 Hz), 5.97 (2H, brs), 6.62-6.68 (2H, m), 6.89 (1H, d, J=7.6 Hz),7.20 (1H, d, J=8.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.40 (2H, dd, J=5.6,12.5 Hz), 7.54 (1H, d, J=8.0 Hz)

Example 155 Synthesis of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one

To a solution of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one(0.4 g) obtained in Reference Example 18 in DMF (10 ml) were added 37%aqueous formalin solution (1.5 ml) and triethylamine (0.02 ml), and themixture was heated at 80° C. for 10 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure to give a mixture (0.46 g, 1:3) of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-oneand7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one.

amorphous: colorless

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.2 Hz), 1.27 (1.5H, s), 1.29 (4.5H,s), 1.68-1.78 (2H, m), 1.78-1.90 (2H, m), 2.46 (1.5H, s), 2.48 (0.5H,s), 2.52 (2H, t, J=7.4 Hz), 2.72 (4H, m), 3.19 (4H, m), 3.95-4.05 (2H,m), 5.41 (0.5H, s), 6.36 (0.75H, d, J=2.5 Hz), 6.58 (0.75H, dd, J=2.5,8.5 Hz), 6.64 (0.25H, dd, J=2.4, 8.5 Hz), 6.87-6.92 (1.25H, m), 7.17(0.75H, d, J=8.5 Hz), 7.18 (0.25H, d, J=8.5 Hz), 7.27 (1H, t, J=7.8 Hz),7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0 Hz), 8.32 (0.75H, brs)

Example 156 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester decyl ester

7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one(460 mg), which is a mixture with7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-oneobtained in Example 155, was suspended in methylene chloride (10 ml),pyridine (0.06 ml) and decyl chloroformate (103 mg) were added, and themixture was stirred under ice-cooling for 4 hr. Water was added to thereaction mixture, and the mixture was extracted with methylene chloride,and dried over magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography (ethyl acetate:n-hexane-2:1) to give carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester decyl ester (108 mg).

colorless oil

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=6.8 Hz), 1.20-1.40 (20H, m), 1.62-1.70(2H, m), 1.70-1.80 (2H, m), 1.80-1.90 (2H, m), 2.50-2.56 (4H, m), 2.73(4H, m), 3.20 (4H, m), 4.00 (2H, t, J=6.2 Hz), 4.17 (2H, t, J=6.8 Hz),5.99 (2H, s), 6.65 (1H, dd, J=2.4, 8.5 Hz), 6.71 (1H, d, J=2.3 Hz), 6.89(1H, d, J=7.6 Hz), 7.20 (1H, d, J=8.4 Hz), 7.27 (1H, t, J=7.8 Hz),7.36-7.44 (2H, m), 7.54 (1H, d, J=8.1 Hz)

Example 157 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester

To a solution of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one(0.38 g) obtained in Reference Example 18 in THF (10 ml) was added 60%sodium hydride (40 mg) with stirring under ice-cooling, and the mixturewas heated under reflux for 0.5 hr. Thereafter, with stirring underice-cooling, a solution of chloromethyl phenylcarbonate (0.23 g) in THF(1 ml) was added dropwise, and the mixture was stirred at roomtemperature overnight. With stirring under ice-cooling, water was addedto the reaction mixture, and the mixture was extracted with ethylacetate, washed with water, and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (ethylacetate:n-hexane-1:1) to give carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester phenyl ester (130 mg).

colorless oil

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.68-1.90 (4H, m), 2.46-2.56 (2H, m),2.57 (2H, s), 2.68-2.78 (4H, br), 3.14-3.24 (4H, br), 4.02 (2H, t, J=6.2Hz), 6.11 (2H, s), 6.68 (1H, dd, J=2.4, 8.5 Hz), 6.75 (1H, d, J=2.4 Hz),6.89 (1H, d, J=7.6 Hz), 7.16-7.46 (9H, m), 7.55 (1H, d, J=8.0 Hz).

Example 158 Synthesis of N-decylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester

To a solution of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one(0.21 g) obtained in Reference Example 18 in THF (10 ml) was added withstirring under ice-cooling 60% sodium hydride (27 mg), and the mixturewas heated under reflux for 0.5 hr. Thereafter, with stirring underice-cooling, a solution of chloromethyl phenylcarbonate (0.17 g) in THF(1 ml) was added dropwise, and the mixture was stirred at roomtemperature overnight. With stirring under ice-cooling, water was addedto the reaction mixture, and the mixture was extracted with ethylacetate, washed with water, and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure. To a solution of theobtained residue in THF (10 ml) was added decylamine (0.5 ml), and themixture was stirred at room temperature overnight. With stirring underice-cooling, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate, washed with water, and dried overmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography (ethylacetate:n-hexane=2:1) to give N-decylcarbamic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester (126 mg).

yellow oil

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=6.8 Hz), 1.18-1.34 (20H, m), 1.42-1.52(2H, m), 1.70-1.80 (2H, m), 1.80-1.90 (2H, m), 2.48-2.56 (4H, m),2.66-2.78 (4H, br), 3.12-3.24 (6H, m), 4.01 (2H, t, J=6.1 Hz), 4.76-4.84(1H, m), 5.96 (2H, s), 6.64 (1H, dd, J=2.3, 8.5 Hz), 6.81 (1H, d, J=2.0Hz), 6.89 (1H, d, J=7.6 Hz), 7.19 (1H, d, J=8.5 Hz), 7.24-7.30 (1H, m),7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz)

Example 163 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester methyl ester

To a solution of n-hexylalcohol (50.5 mg) in tetrahydrofuran (5 ml) wasadded with stirring under ice-cooling 60% sodium hydride (18 mg) bysmall portions, and the mixture was stirred at the same temperature for0.5 hr, to a solution of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester (240 mg) in tetrahydrofuran (1 ml) was added withstirring under ice-cooling sodium methoxide (30 mg), and the mixture wasstirred for 3 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate, and dried over sodium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (ethyl acetate) to givecarbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester methyl ester (42 mg).

oil: colorless

¹H-NMR (CDCl₃) δ ppm: 1.72-1.84 (2H, m), 1.85-1.96 (2H, m), 2.55 (2H, t,J=7.4 Hz), 2.68-2.80 (4H, br), 3.14-3.26 (4H, br), 3.83 (3H, s), 4.10(2H, t, J=6.2 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd,J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.92 (1H, d, J=2.0 Hz), 7.27(1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.50 (1H, d, J=8.0 Hz), 7.60 (1H,d, J=9.5 Hz)

Example 165 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester propyl ester

In the same manner as in Example 175, the compound was obtained (yield78 mg, 27.5%) as a colorless oil.

¹H-NMR (CDCl₃) δ ppm: 0.94 (3H, t, J=7.4 Hz), 1.58-1.84 (4H, m),1.84-1.96 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.66-2.80 (4H, br), 3.14-3.28(4H, br), 4.09 (2H, t, J=6.0 Hz), 4.15 (2H, t, J=6.7 Hz), 6.34 (2H, s),6.49 (1H, d, J=9.5 Hz), 6.83 (1H, dd, J=2.1, 8.6 Hz), 6.89 (1H, d, J=7.6Hz), 6.93 (1H, d, J=2.0 Hz), 7.26 (1H, t, J=7.8 Hz), 7.36-7.44 (3H, m),7.54 (1H, d, J=8.0 Hz), 7.62 (1H, d, J=9.5 Hz)

Example 168 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester butyl ester

In the same manner as in Example 175, the compound was obtained (yield47 mg, 14.3%) as a colorless oil.

¹H-NMR (CDCl₃) δ ppm: 0.92 (3H, t, J=7.4 Hz), 1.32-1.44 (2H, m),1.60-1.70 (2H, m), 1.72-1.84 (2H, m), 1.86-1.96 (2H, m), 2.55 (2H, t,J=7.5 Hz), 2.68-2.80 (4H, br), 3.16-3.26 (4H, br), 4.06-4.15 (2H, m),4.20 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H,dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.7 Hz), 6.93 (1H, d, J=2.1 Hz), 7.27(1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H,d, J=9.5 Hz)

Example 170 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester isobutyl ester

In the same manner as in Example 175, the compound was obtained (yield48 mg, 14.6%) as a colorless oil.

¹H-NMR (CDCl₃) δ ppm: 0.94 (6H, d, J=6.7 Hz), 1.70-2.04 (5H, m), 2.55(2H, t, J=7.4 Hz), 2.66-2.80 (4H, br), 3.14-3.24 (4H, br), 3.98 (2H, d,J=6.6 Hz), 4.10 (2H, t, J=6.2 Hz), 6.35 (2H, s), 6.51 (1H, d, J=9.5 Hz),6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.0Hz), 7.27 (1H, t, J=7.8 Ic Hz), 7.37-7.46 (3H, m), 7.55 (1H, d, J=8.1Hz), 7.61 (1H, d, J=9.5 Hz)

Example 175 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester hexyl ester

To a solution of n-hexylalcohol (50.5 mg) in tetrahydrofuran (5 ml) wasadded with stirring under ice-cooling 60% sodium hydride (18 mg) bysmall portions, and the mixture was stirred at the same temperature for0.5 hr, a solution of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester phenyl ester (240 mg) in tetrahydrofuran (1 ml) was addeddropwise, and the mixture was stirred under ice-cooling for 3 hr. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate, and dried over sodium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography (ethyl acetate) to give carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester hexyl ester (30 mg).

oil: colorless

¹H-NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.20-1.40 (6H, m),1.60-1.72 (2H, m), 1.72-1.84 (2H, m), 1.84-2.00 (2H, m), 2.55 (2H, t,J=7.4 Hz), 2.65-2.82 (4H, br), 3.10-3.28 (4H, br), 4.10 (2H, t, J=6.2Hz), 4.19 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84(1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.1 Hz),7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61(1H, d, J=9.6 Hz)

Example 177 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester nonyl ester

In the same manner as in Example 175, the compound was obtained (yield40 mg, 10.8%) as a colorless oil.

¹H-NMR (CDCl₃) δ ppm: 0.86 (3H, t, J=6.9 Hz), 1.20-1.40 (12H, m),1.60-1.70 (2H, m), 1.72-1.82 (2H, m), 1.85-1.95 (2H, m), 2.55 (2H, t,J=7.4 Hz), 2.68-2.78 (4H, br), 3.14-3.28 (4H, br), 4.06-4.14 (2H, m),4.18 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84 (1H,dd, J=2.1, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.0 Hz), 7.27(1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61 (1H,d, J=9.5 Hz)

Example 179 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester tetradecyl ester

In the same manner as in Example 175, the colorless amorphous compoundwas obtained (yield 33 mg, 9.3%).

¹H-NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.20-1.40 (22H, m),1.55-1.95 (6H, m), 2.56 (2H, t, J=7.4 Hz), 2.68-2.80 (4H, br), 3.15-3.25(4H, br), 4.10 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.7 Hz), 6.35 (2H, s),6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6Hz), 6.93 (1H, d, J=2.0 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m),7.55 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=9.5 Hz)

Example 180 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester hexadecyl ester

In the same manner as in Example 175, the colorless amorphous compoundwas obtained (yield 48 mg, 15%).

¹H-NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.8 Hz), 1.20-1.38 (26H, m),1.60-1.96 (6H, m), 2.55 (2H, t, J=7.4 Hz), 2.70-2.80 (4H, br), 3.16-3.24(4H, br), 4.10 (2H, t, J=6.2 Hz), 4.18 (2H, t, J=6.7 Hz), 6.35 (2H, s),6.50 (1H, d, J=9.5 Hz), 6.84 (1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6Hz), 6.93 (1H, d, J=2.0 Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m),7.55 (1H, d, J=8.1 Hz), 7.61 (1H, d, J=9.5 Hz)

In the same manner as in the above-mentioned Examples, the compoundsdescribed in the following Table 1 can be synthesized.

TABLE 1 Example Structure Formula 159

N-Benzyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2- oxo-3,4-dihydro-2H-quinolin-1- ylmethylester 160

N-Phenethylcarbamic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 161

(7-{4-[4-(Benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-1- yl)methyl N-methoxycarbamate 162

N-Allylcarbamic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 163

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester methylester 164

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester propyl ester 165

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester propylester 166

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester isopropyl ester 167

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester isopropylester 168

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester butyl ester169

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester isobutyl ester 170

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester isobutylester 171

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester pentyl ester 172

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester pentylester 173

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 3-methylbutyl ester 174

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 3-methylbutyl ester 175

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester hexyl ester176

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester nonyl ester 177

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester nonyl ester178

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester tetradecyl ester 179

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester tetradecylester 180

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester hexadecylester 181

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester benzyl ester 182

Carbonic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester benzylester 183

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-methoxymethyl-3,4-dihydro- 1H-quinolin-2-one 184

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-methoxymethyl-1H-quinolin-2- one 185

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-methoxymethoxyquinoline 186

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-ethoxymethyl-3,4-dihydro-1H- quinolin-2-one 187

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-ethoxymethyl-1H-quinolin-2- one 188

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-isopropoxymethyl-3,4-dihydro- 1H-quinolin-2-one 189

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-isopropoxymethyl-1H-quinolin- 2-one 190

Aminoacetic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 191

Aminoacetic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 192

2-Aminopropionic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 193

2-Aminopropionic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 194

2-Amino-3-methylbutyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 195

2-Amino-3-methylbutyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 196

2-Amino-4-methylpentanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2- oxo-3,4-dihydro-2H-quinolin-1- ylmethylester 197

2-Amino-4-methylpentanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2- oxo-2H-quinolin-1-ylmethyl ester 198

Pyrrolidine-2-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 199

Pyrrolidine-2-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 200

Calcium {7-[4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-1- yl)methyl phosphate 201

Calcium {7-[4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}-2-oxo-2H-quinolin-1-yl)methyl phosphate 202

Calcium (7-{4-[4- (benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}quinolin-2- yloxy)methyl phosphate 203

Propionic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 204

Pentanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 205

Heptanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 206

Nonanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 207

Undecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 208

Tridecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 209

Nonadecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 210

Henicosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 211

Docosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 212

Tricosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 213

Tetracosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 214

2,2-Dimethylbutyric acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 215

2,2-Dimethylpentanoic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 216

2,2-Dimethyldodecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 217

Isobutyric acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 218

3-Methylbutyric acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 219

Decanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- yl}ethylester 220

Dodecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- yl}ethylester 221

Tetradecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- yl}ethylester 222

Hexadecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- yl}ethylester 223

(2-Methoxyethoxy)acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 224

[2-(2- Methoxyethoxy)ethoxy]acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2- oxo-3,4-dihydro-2H-quinolin-1- ylmethylester 225

(9Z,12Z)-Octadeca-9,12- dienoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 226

(9Z,12Z,15Z)-Octadeca- 9,12,15-trienoic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1- ylmethyl ester 227

(4Z,7Z,10Z,13Z,16Z,19Z)- Docosa-4,7,10,13,16,19- hexaenoic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1- ylmethyl ester 228

(6Z,9Z,12Z,15Z)-Octadeca- 6,9,12,15-tetraenoic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1- ylmethyl ester 229

Isonicotinic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 230

Pyrimidine-5-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 231

Pyridazine-4-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 232

Propionic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 233

Pentanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 234

Heptanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 235

Nonanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 236

Undecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 237

Tridecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 238

Nonadecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 239

Henicosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 240

Docosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 241

Tricosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 242

Tetracosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 243

2,2-Dimethylbutyric acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 244

2,2-Dimethylpentanoic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 245

2,2-Dimethyldodecanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 246

Isobutyric acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 247

3-Methylbutyric acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 248

Decanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-yl}ethyl ester 249

Dodecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-yl}ethyl ester 250

Tetradecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-yl}ethyl ester 251

Hexadecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-yl}ethyl ester 252

1-Methylpiperidine-4-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2- oxo-2H-quinolin-1-ylmethyl ester 253

(2-Methoxyethoxy)acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 254

[2-(2- Methoxyethoxy)ethoxy]acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2- oxo-2H-quinolin-1-ylmethyl ester 255

(2-Butoxyethoxy)acetic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 256

(9Z,12Z)-Octadeca-9,12- dienoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 257

(9Z,12Z,15Z)-Octadeca- 9,12,15-trienoic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester 258

(4Z,7Z,10Z,13Z,16Z,19Z)- Docosa-4,7,10,13,16,19- hexaenoic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester 259

(6Z,9Z,12Z,15Z)-Octadeca- 9,12,15-tetraenoic acid 7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester 260

Isonicotinic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 261

Nicotinic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 262

Pyrimidine-5-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 263

Pyridazine-4-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 264

Pyridine-2-carboxylic acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 265

Pyridine-2-carboxylic acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 266

Furan-2-carboxylic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 267

Furan-2-carboxylic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 268

Thiophene-3-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 269

Thiophene-3-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 270

Quinoline-6-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 3,4-dihydro-2H-quinolin-1- ylmethylester 271

Quinoline-6-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo- 2H-quinolin-1-ylmethyl ester 272

Benzoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 273

2,2-Dimethylpropionic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 274

Butyric acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 275

Phenylacetic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 276

Octanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 277

Cyclohexanecarboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 278

Cyclopentanecarboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 279

(Z)-Octadec-9-enoic acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 280

Hexadecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 281

Icosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 282

2-Pentyl-heptanoic acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 283

Decanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 284

Hexanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 285

Octadecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 286

Acetic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 287

Propionic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 288

Pentanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 289

Heptanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 290

Nonanoic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 291

Undecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 292

Tridecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 293

Tetradecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 294

Pentadecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 295

Heptadecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 296

Nonadecanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 297

Henicosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 298

Docosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 299

Tricosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 300

Tetracosanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 301

Malonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester tert- butylester 302

2-Methyl-butyric acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 303

2-Methyl-pentanoic acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 304

2-Methyl-hexanoic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 305

2,2-Dimethyl-hexanoic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 306

Isobutyric acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 307

3-Methyl-butyric acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 308

4-Methyl-pentanoic acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 309

Cyclobutanecarboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 310

Decanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-ethyl ester 311

Dodecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-ethyl ester 312

Tetradecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-ethyl ester 313

Hexadecanoic acid 1-{7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-ethyl ester 314

Tetrahydro-pyran-4-carboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 315

(2-Methoxy-ethoxy)-acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 316

[2-(2-Methoxy-ethoxy)-ethoxy]- acetic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 317

(2-Butoxy-ethoxy)-acetic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 318

Cycloheptanecarboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 319

4,4,4-Trifluoro-butyric acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 320

Piperidine-1-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 321

N-Butyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 322

N,N-Dibutylcarbamic acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 323

N-Cyclohexylmethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 324

N-Butylcarbamic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 325

N-Methylcarbamic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 326

N,N-Dimethylcarbamic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 327

N-Ethylcarbamic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 328

N,N-Diethylcarbamic acid 7-[4- (4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 329

N-Pentadecylcarbamic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 330

N-Octadecylcarbamic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 331

N-Methyl-N-octadecylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 332

N-Cyclohexylcarbamic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 333

N-Benzylcarbamic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 334

N-Benzyl-N-methylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 335

N-Phenethylcarbamic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 336

Morpholine-4-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 337

N-(2-Methoxyethyl)carbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 338

{7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1- ylmethoxycarbonylamino}aceticacid methyl ester 339

({7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethoxycarbonyl}-methyl-amino)acetic acid methyl ester 340

(7-{4-[4-(Benzo[b]thiophen-4- yl)piperazin-1-yl]butoxy}-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-yl)methyl N- methoxycarbamate341

7-[4-(4-benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl N- benzyloxycarbamate342

N-(3,3,3-Trifluoro- propyl)carbamic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 343

N-Furan-2-ylmethylcarbamic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 344

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester methyl ester345

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester ethyl ester 346

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester propyl ester347

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester isopropyl ester348

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester butyl ester 349

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester isobutyl ester350

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester pentyl ester351

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 3- methyl-butylester 352

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester hexyl ester 353

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester nonyl ester 354

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester tetradecylester 355

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester hexadecyl ester356

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester benzyl ester357

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester heptyl ester358

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester octyl ester 359

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester 2,2,2-trifluoro-ethyl ester 360

Carbonic acid 7-[4-(4- benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H- quinolin-1-ylmethyl ester cyclohexylester 361

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-methoxymethyl-4,4-dimethyl- 3,4-dihydro-1H-quinolin-2-one 362

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-ethoxymethyl-4,4-dimethyl-3,4- dihydro-1H-quinolin-2-one 363

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-isopropoxymethyl-4,4-dimethyl- 3,4-dihydro-1H-quinolin-2-one 364

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-1-benzyloxymethyl-4,4-dimethyl- 3,4-dihydro-1H-quinolin-2-one 365

7-[4-(4-Benzo[b]thiophen-4- ylpiperazin-1-yl)butoxy]-4,4-dimethyl-1-(2,2,2-trifluoro- ethoxymethyl)-3,4-dihydro-1H-quinolin-2-one 366

Amino-acetic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethylester 367

2-Amino-propionic acid 7-[4-(4- benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 368

2-Amino-3-methyl-butyric acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 369

2-Amino-4-methyl-pentanoic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester 370

Pyrrolidine-2-carboxylic acid 7- [4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4- dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester

Example 371 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyldodecanoate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(800 mg) synthesized in the same manner as in WO2006/112464 (Example 1)in dimethylformamide (30 ml) was added silver carbonate (I) (0.76 g),chloromethyldodecanoate[61413-67-0] (1.15 g) was added, and the mixturewas stirred at 60° C. for 6 hr. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate and dried over Na₂SO₄.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (ethylacetate:n-hexane-2:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyldodecanoate (22 mg).

oil: colorless

¹H-NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=7.1 Hz), 1.16-2.10 (18H, m), 2.36(2H, t, J=7.5 Hz), 2.58 (2H, t, J=7.5 Hz), 2.76 (4H, br), 3.21 (4H, br),4.15 (2H, t, J=6.3 Hz), 6.25 (2H, s), 6.80 (1H, d, J=8.7 Hz), 6.90 (1H,d, J=7.4 Hz), 7.06 (1H, dd, J=2.5, 8.8 Hz), 7.22 (1H, d, J=2.3 Hz), Hz),7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz), 7.61(1H, d, J=8.8 Hz), 7.96 (1H, d, J=8.7 Hz)

Example 372 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylcyclohexyl carbonate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(700mg) synthesized in the same manner as in WO2006/112464 (Example 1) indimethylformamide (20 ml) was added silver carbonate (I) (0.53 g),chloromethyl cyclohexyl carbonate[40510-86-9] (0.68 g) was added, andthe mixture was stirred at 60° C. for 6 hr. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate, anddried over Na₂SO₄. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography (ethylacetate:n-hexane-2:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylcyclohexyl carbonate (60 mg).

amorphous: colorless

¹H-NMR (CDCl₃) δ ppm: 1.10-2.00 (14H, m), 2.56 (2H, t, J=7.5 Hz), 2.75(4H, br), 3.21 (4H, br), 4.14 (2H, t, J=6.3 Hz), 4.64-4.74 (1H, m), 6.27(2H, s), 6.82 (1H, d, J=8.7 Hz), 6.90 (1H, d, J=7.2 Hz), 7.06 (1H, dd,J=2.5, 8.8 Hz), 7.20-7.30 (2H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J=8.0Hz), 7.61 (1H, d, J=8.9 Hz), 7.96 (1H, d, J=8.7 Hz)

Example 373 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylhexylcarbonate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(730 mg) synthesized in the same manner as in WO2006/112464 (Example 1)in dimethylformamide (20 ml) was added silver carbonate (I) (0.56 g),chloromethyl hexyl carbonate[663597-51-1] (0.72 g) was added, and themixture was stirred at 60° C. for 10 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, and driedover Na₂SO₄. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography (ethylacetate:n-hexane=2:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylhexyl carbonate (95 mg).

oil: yellow

¹H-NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.20-1.40 (6H, m),1.60-1.70 (2H, m), 1.74-1.84 (2H, m), 1.88-1.98 (2H, m), 2.57 (2H, t,J=7.6 Hz), 2.76 (4H, br), 3.21 (4H, br), 4.14 (2H, t, J=6.3 Hz), 4.19(2H, t, J=6.7 Hz), 6.27 (2H, s), 6.82 (1H, d, J=8.7 Hz), 6.90 (1H, d,J=7.6 Hz), 7.06 (1H, dd, J=2.5, 8.8 Hz), 7.23 (1H, d, J=2.4 Hz), Hz),7.27 (1H, t, J=7.9 Hz), 7.35-7.45 (2H, m), 7.55 (1H, d, J=8.0 Hz), 7.61(1H, d, J=8.8 Hz), 7.96 (1H, d, J=8.7 Hz)

Example 374 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylphenylcarbonate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(1.5 g) synthesized in the same manner as in WO2006/112464 (Example 1)in dimethylformamide (50 ml) was added silver carbonate (I) (1.14 g),chloromethyl phenyl carbonate[35180-03-1] (1.42 g) was added, and themixture was stirred at 60° C. for 4 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, and driedover Na₂SO₄. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography (ethylacetate:n-hexane=2:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylphenyl carbonate (20 mg).

oil: colorless

¹H-NMR (CDCl₃) δ ppm: 1.70-2.10 (4H, m), 2.59 (2H, t, J=7.4 Hz), 2.78(4H, br), 3.22 (4H, br), 4.10-4.18 (2H, m), 6.38 (2H, s), 6.80-6.95 (4H,m), 7.08 (1H, dd, J=2.4, 8.8 Hz), 7.18-7.45 (7H, m), 7.55 (1H, d, J=8.0Hz), 7.63 (1H, d, J=8.9 Hz), 8.00 (1H, d, J=8.7 Hz)

Example 375 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyldecylcarbamate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethylphenyl carbonate (20 mg) synthesized in the same manner as in Example374 in THF (10 ml) was added decylamine[2016-57-1] (0.1 ml), and themixture was stirred at room temperature overnight. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate,and dried over Na₂SO₄. The solvent was evaporated under reduced pressureand the residue was purified by silica gel column chromatography (ethylacetate:n-hexane=2:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yloxymethyldecyl carbamate (18 mg).

oil: colorless

¹H-NMR (CDCl₃) δ ppm: 0.87 (3H, t, J=6.9 Hz), 1.10-2.40 (20H, m), 2.58(2H, t, J=7.4 Hz), 2.76 (4H, br), 3.16-3.26 (6H, m), 4.15 (2H, t, J=6.3Hz), 4.83 (1H, t, J=5.4 Hz), 6.23 (2H, s), 6.82 (1H, d, J=8.7 Hz), 6.90(1H, d, J=7.6 Hz), 7.06 (1H, dd, J=2.5, 8.8 Hz), 7.23 (1H, d, J=2.4 Hz),Hz), 7.27 (1H, t, J=7.8 Hz), 7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz),7.61 (1H, d, J=8.8 Hz), 7.95 (1H, d, J=8.7 Hz)

Example 376 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-dodecanoyl-3,4-dihydroquinolin-2(1H)-one

To a solution of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one(0.3 g) synthesized in the same manner as in WO2006/112464 (Example 11)in methylene chloride (10 ml) was added pyridine (0.11 ml), withstirring under ice-cooling, dodecanoylchloride (0.24 ml) was added, andthe mixture was stirred at room temperature overnight. Water was addedto the reaction mixture and the mixture was extracted with methylenechloride, and dried over sodium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography (ethyl acetate) to give7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-dodecanoyl-3,4-dihydro-1H-quinolin-2-one(0.4 g).

oil: colorless

¹H-NMR (CDCl₃) δ ppm: 0.88 (3H, t, J=6.8 Hz), 1.20-1.40 (16H, m),1.68-1.90 (6H, m), 2.54 (2H, t, J=7.4 Hz), 2.65-2.80 (6H, m), 2.80-2.88(2H, m), 2.97 (2H, t, J=7.6 Hz), 3.16-3.26 (4H, m), 3.97 (2H, t, J=6.2Hz), 6.67 (1H, dd, J=2.4, 8.3 Hz), 6.83 (1H, dd, J=0.6, 7.7 Hz), 7.08(1H, d, J=8.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.37-7.43 (2H, m), 7.55 (1H,d, J=8.0 Hz)

Example 377 Synthesis of7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-1-(cyclohexanecarbonyl)-3,4-dihydroquinolin-2(H)-one

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-3,4-dihydro-1H-quinolin-2-one(1 g) synthesized in the same manner as in WO2006/112464 (Example 11) indichloromethane (30 ml) was added pyridine (0.37 ml), with stirringunder ice-cooling, cyclohexanecarbonyl chloride (0.46 ml) was added andthe mixture was stirred at room temperature overnight. Water was addedto the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate, the solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane-9:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1-(cyclohexanecarbonyl)-3,4-dihydroquinolin-2(1H)-one(1.2 g).

oil: yellow

¹H-NMR (CDCl₃) δ ppm: 1.20-2.25 (14H, m), 2.53 (2H, t, J=7.5 Hz),2.64-2.78 (6H, m), 2.84-2.90 (2H, m), 3.12-3.24 (5H, m), 3.97 (2H, t,J=6.2 Hz), 6.59 (1H, d, J=2.3 Hz), 6.63 (1H, dd, J=2.4, 8.3 Hz), 6.90(1H, d, J=7.4 Hz), 7.08 (1H, d, J=8.3 Hz), 7.27 (1H, t, J=7.8 Hz),7.36-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz)

Example 378 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]quinolin-2-ylacetate

To a solution of7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one(3.14 g) synthesized in the same manner as in WO2006/112464 (Example 1)in methylene chloride (32 mL) were added with stirring under ice-coolingtriethylamine (4.0 mL) and acetyl chloride (1.5 mL), and the mixture wasstirred at room temperature for 39 hr. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (methylene chloride:ethyl acetate-7:3→1:9) to give7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]quinolin-2-yl acetate(1.24 g).

oil: yellow

¹H-NMR (CDCl₃) δ ppm: 1.62-1.81 (2H, m), 1.81-2.00 (2H, m), 2.39 (3H,s), 2.54 (2H, t, J=7.5 Hz), 2.67-2.86 (4H, m), 3.10-3.29 (4H, m), 4.15(2H, t, J=6.3 Hz), 6.90 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=8.5 Hz),7.10-7.29 (3H, m), 7.29-7.48 (2H, m), 7.55 (1H, d, J=7.8 Hz), 7.72 (1H,d, J=9.0 Hz), 8.15 (1H, d, J=8.5 Hz)

Example 379 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yldodecanoate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(800 mg) in dichloromethane (20 ml) synthesized in the same manner as inWO2006/112464 (Example 1) was added triethylamine (0.77 ml), withstirring under ice-cooling, dodecanoylchloride (1.1 ml) was added andthe mixture was stirred at room temperature for 4 hr. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was dried over sodium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (ethyl acetate) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yldodecanoate (1.34 g).

oil: yellow

¹H-NMR (CDCl₃) δ ppm: 0.88 (3H, t, J=6.8 Hz), 1.20-1.50 (16H, m),1.72-1.86 (4H, m), 1.86-1.98 (2H, m), 2.55 (2H, t, J=7.6 Hz), 2.66 (2H,t, J=7.6 Hz), 2.75 (4H, br), 3.20 (4H, br), 4.14 (2H, t, J=6.3 Hz), 6.90(1H, d, J=7.5 Hz), 7.04 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=2.4, 8.9 Hz),7.27 (1H, t, J=7.8 Hz), 7.33 (1H, d, J=2.4 Hz), 7.36-7.44 (2H, m), 7.55(1H, d, J=8.1 Hz), 7.71 (1H, d, J=9.0 Hz), 8.14 (1H, d, J=8.6 Hz)

Example 380 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-ylcyclohexanecarboxylate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(800 mg) synthesized in the same manner as in WO2006/112464 (Example 1)in dichloromethane (20 ml) was added triethylamine (0.64 ml), withstirring under ice-cooling, cyclohexanecarbonyl chloride (0.49 ml) wasadded and the mixture was stirred at room temperature overnight. Waterwas added to the reaction mixture and the mixture was extracted withethyl acetate. The organic layer was dried over sodium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (ethylacetate:n-hexane=4:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-ylcyclohexanecarboxylate (1.08 g).

oil: yellow

¹H-NMR (CDCl₃) δ ppm: 1.20-2.20 (14H, m), 2.54 (2H, t, J=7.5 Hz),2.60-2.80 (5H, m), 3.20 (4H, br), 4.08-4.18 (2H, m), 6.89 (1H, d, J=7.6Hz), 7.01 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=2.5, 8.9 Hz), 7.27 (1H, t,J=7.8 Hz), 7.34 (1H, d, J=2.4 Hz), 7.36-7.44 (2H, m), 7.54 (1H, d, J=8.0Hz), 7.70 (1H, d, J=8.9 Hz), 8.12 (1H, d, J=8.6 Hz)

Example 381 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-ylhexyl carbonate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(800 mg) synthesized in the same manner as in WO2006/112464 (Example 1)in dichloromethane (20 ml) was added triethylamine(0.65 ml), withstirring under ice-cooling, hexylchloroformate (0.6 g) was added at roomtemperature overnight. Water was added to the reaction mixture and themixture was extracted with ethyl acetate. The organic layer was driedover sodium sulfate. The solvent was evaporated under reduced pressureand the residue was purified by silica gel column chromatography (ethylacetate:n-hexane=1:2) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-ylhexyl carbonate (1.09 g).

oil: colorless

¹H-NMR (CDCl₃) δ ppm: 0.91 (3H, t, J=7.0 Hz), 1.30-1.50 (6H, m),1.70-1.84 (4H, m), 1.88-1.98 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.72 (4H,br), 3.20 (4H, br), 4.15 (2H, t, J=6.4 Hz), 4.30 (2H, t, J=6.7 Hz), 6.90(1H, dd, J=0.4, 7.6 Hz), 7.08 (1H, d, J=8.6 Hz), 7.20 (1H, dd, J=2.4,8.9 Hz), 7.27 (1H, t, J=7.8 Hz), 7.33 (1H, d, J=2.4 Hz), 7.36-7.44 (2H,m), 7.54 (1H, d, J=8.0 Hz), 7.72 (1H, d, J=9.0 Hz), 8.15 (1H, d, J=8.6Hz)

Example 382 Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yldiethylcarbamate

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(800 mg) synthesized in the same manner as in WO2006/112464 (Example 1)in dichloromethane (20 ml) was added triethylamine (0.65 ml), withstirring under ice-cooling, diethylcarbamoylchloride (0.5 g) was addedand the mixture was stirred at room temperature overnight. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=20:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yldiethylcarbamate (120 mg).

oil: colorless

¹H-NMR (CDCl₃) δ ppm: 1.23 (3H, t, J=7.1 Hz), 1.30 (3H, t, J=7.1 Hz),1.72-1.84 (2H, m), 1.86-1.98 (2H, m), 2.54 (2H, t, J=7.5 Hz), 2.73 (4H,br), 3.20 (4H, br), 3.43 (2H, q, J=7.0 Hz), 3.52 (2H, q, J=7.1 Hz), 4.13(2H, t, J=6.3 Hz), 6.89 (1H, d, J=7.2 Hz), 7.08 (1H, d, J=8.6 Hz), 7.16(1H, dd, J=2.5, 8.9 Hz), 7.26 (1H, t, J=7.8 Hz), 7.34 (1H, d, J=2.4 Hz),7.36-7.44 (2H, m), 7.54 (1H, d, J=7.9 Hz), 7.68 (1H, d, J=8.9 Hz), 8.09(1H, d, J=8.6 Hz)

Example 383 Synthesis of4-(benzo[b]thiophen-4-yl)-1-(dodecanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)piperazin-1-iumiodide

To a solution of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(0.85 g) synthesized in the same manner as in WO2006/112464 (Example 1)in dichloromethane (20 ml) was added iodomethyldodecanoate (1 g)synthesized in the same manner as in Reference Example 19, and themixture was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure, ether was added and the mixture wasleft standing. The obtained crystals were collected by filtration togive4-(benzo[b]thiophen-4-yl)-1-(dodecanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)piperazin-1-iumiodide (1.07 g).

powder:yellow

¹H-NMR (DMSO-d₆) δ ppm: 0.84 (3H, t, J=6.8 Hz), 1.10-2.56 (24H, m),3.44-3.56 (4H, m), 3.60-3.90 (6H, m), 4.09 (2H, t, J=5.5 Hz), 5.57 (2H,s), 6.31 (1H, d, J=9.4 Hz), 6.80-6.86 (2H, m), 7.05 (1H, d, J=7.6 Hz),7.35 (1H, t, J=7.9 Hz), 7.54 (1H, d, J=5.5 Hz), 7.56-7.62 (1H, m),7.68-7.86 (3H, m), 11.63 (1H, s)

Example 384 Synthesis of(7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyloctyl carbonate

In the same manner as in Example 175, the compound was obtained (yield25 mg, 8.7%) as a colorless oil.

¹H-NMR (CDCl₃) δ ppm: 0.86 (3H, t, J=6.9 Hz), 1.16-1.40 (10H, m),1.58-1.72 (2H, m), 1.72-1.84 (2H, m), 1.85-1.95 (2H, m), 2.55 (2H, t,J=7.5 Hz), 2.68-2.80 (4H, br), 3.14-3.26 (4H, br), 4.10 (2H, t, J=6.2Hz), 4.18 (2H, t, J=6.7 Hz), 6.35 (2H, s), 6.50 (1H, d, J=9.5 Hz), 6.84(1H, dd, J=2.2, 8.6 Hz), 6.89 (1H, d, J=7.6 Hz), 6.93 (1H, d, J=2.1 Hz),7.27 (1H, t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.55 (1H, d, J=8.0 Hz), 7.61(1H, d, J=9.5 Hz)

Example 385 Synthesis of carbonic acid7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethylester cyclohexyl ester hydrochloride

Sodium hydride (55% oil) (0.962 g, 22.04 mmol) was suspended intetrahydrofuran (THF) (200 ml),7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(8.31 g, 19.17 mmol) was added and the mixture was stirred at 50° C. for1 hr. The mixture was cooled to 0° C., chloromethyl cyclohexyl carbonate(4.80 g, 24.92 mmol) was added dropwise and the mixture was stirred atroom temperature overnight. After cooling to 0° C., excess 2Nhydrochloric acid was added to quench the reaction. The precipitatedsolid was collected by filtration and dried. In addition, the filtratewas extracted with ethyl acetate. The organic layer was concentrated andpurified by moderate-pressure silica gel column chromatography(methylene chloride:methanol=100:0 to 20:1). Likewise, the solid waspurified by moderate-pressure silica gel column chromatography.Concentration under reduced pressure gave the title compound (yield,5.04 g, 42%) as a white solid.

¹H-NMR (DMSO-d₆) δ ppm: 1.16 (m, 6H), 1.59-1.69 (m, 2H), 1.80 (m, 6H),3.00-3.60 (m, 10H), 4.19 (t, J=5.9 Hz, 2H), 4.57-4.65 (m, 18), 6.29 (s,2H), 6.42 (d, J=9.5 Hz, 1H), 6.97 (dd, J=2.3, 8.5 Hz, 1H), 6.98 (dd,J=1.8, 7.7 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 7.31 (dd, J=7.7, 7.7 Hz,1H), 7.43 (dd, J=1.8, 5.5 Hz, 1H), 7.63-7.71 (m, 3H), 7.86 (d, J=9.5 Hz,1H).

In the same manner as in the above-mentioned Examples, the compoundsdescribed in the following Table 2 can be synthesized.

TABLE 2 Example Structure Formula 386

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl dipropylcarbamate 387

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl diisobutylcarbamate 388

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl dihexylcarbamate 389

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl nonadecylcarbonate 390

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl methyl(nonyl)carbamate 391

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl methyl(tetradecyl)carbamate 392

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl ditetradecylcarbamate 393

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl dinonylcarbamate 394

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl 2,2-dimethyldecanoate 395

1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-2- ethoxy-2-oxoethyl decanoate 396

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl 2,2-dimethyloctanoate 397

1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)ethyl butyrate 398

1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)ethyl 3- methylbutanoate 399

1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)ethyl hexanoate 400

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl 2-hydroxyethylcarbamate 401

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl bis(2-hydroxyethyl)carbamate 402

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl 4-methylpiperazine-1- carboxylate 403

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl 1,4′-bipiperidine-1′- carboxylate 404

calcium 1-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-2- methylpropyl phosphate 405

1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)ethyl dimethylcarbamate 406

1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)ethyl methyl(tetradecyl)carbamate 407

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl 4-acetamidobutanoate 408

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl 4-heptanamidobutanoate 409

1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)ethyl dinonylcarbamate 410

1-(7-(4-(4-(benzo[b]thiophen- 4-yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)ethyl ditetradecylcarbamate 411

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl 4-heptanamidobutanoate 412

(5Z,8Z,11Z,14Z,17Z)-(7-(4- (4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methylhenicosa-5,8,11,14,17- pentaenoate 413

(7Z,10Z,13Z,16Z,19Z)-(7-(4- (4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)-2- oxoquinolin-1(2H)-yl)methylpentacosa-7,10,13,16,19- pentaenoate 414

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl acetate 415

(7-(4-(4-(benzo[b]thiophen4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl propionate 416

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazn-1- yl)butoxy)quinolin-2-yloxy)methyl butyrate 417

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl pentanoate 418

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl hexanoate 419

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl heptanoate 420

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl octanoate 421

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl nonanoate 422

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl decanoate 423

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl undecanoate 424

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl tridecanoate 425

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl tetradecanoate 426

(7-(4-(4-(benzo[b]thiophen--4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl pentadecanoate 427

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl palmitate 428

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl heptadecanoate 429

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl stearate 430

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl icosanoate 431

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl 2,2- dimethyltetradecanoate 432

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl pivalate 433

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl 2,2- dimethylbutanoate 434

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl isobutyrate 435

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl-2- hydroxyacetate 436

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl cyclopropanecarboxylate 437

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl cyclobutanecarboxylate 438

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl cyclopentanecarboxylate 439

(7-(4-(4-(benzo[b]thiophen-4 yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl cyclohexanecarboxylate 440

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl benzoate 441

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl 2-phenylacetate 442

(9Z,12Z,15Z)-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2- yloxy)methyl octadeca- 9,12,15-trienoate 443

(5Z,8Z,11Z,14Z,17Z)-(7- 4- (4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2- yloxy)methyl henicosa- 5,8,11,14,17-pentaenoate444

(4Z,7Z,10Z,13Z,16Z,19Z)-(7- (4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2- yloxy)methyl docosa- 4,7,10,13,16,19-hexaenoate445

(6Z,9Z,12Z,15Z)-(7-(4-(4- (benzo[b]thiophen-4- yl)piperidin-1-yl)butoxy)quinolin-2 yloxy)methyl octadeca- 6,9,12,15-tetraenoate 446

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl methyl carbonate 447

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl ethyl carbonate 448

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl butyl carbonate 449

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl pentyl carbonate 450

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl 2-methoxyethyl carbonate 451

calcium (7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2- yloxy)methyl phosphate 452

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl methylcarbamate 453

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl ethylcarbamate 454

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl propylcarbamate 455

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl butylcarbamate 456

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl pentylcarbamate 457

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl hexylcarbamate 458

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl octylcarbamate 459

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl dodecylcarbamate 460

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl tetradecylcarbamate 461

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2yloxy)methyl hexadecylcarbamate 462

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl dimethylcarbamate 463

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl diethylcarbamate 464

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl dipropylcarbamate 465

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl diisobutylcarbamate 466

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl dibutylcarbamate 467

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl dihexylcarbamate 468

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl dioctylcarbamate 469

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl didecylcarbamate 470

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl didodecylcarbamate 471

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl ditetradecylcarbamate 472

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl dihexadecylcarbamate 473

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl bis(2- hydroxyethyl)carbamate 474

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl piperidine-1- carboxylate 475

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl 4- methylpiperazine-1- carboxylate 476

(7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl 1,4′-bipiperidine- 1′-carboxylate 477

1-acetyl-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one 478

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-propionylquinolin-2(1H)-one 479

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-butyrylquinolin-2(1H)-one 480

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-pentanoylquinolin-2(1H)-one 481

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(3-methylbutanoyl)quinolin- 2(1H)-one 482

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-hexanoylquinolin-2(1H)-one 483

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-hexanoyl-3,4-dihydroquinolin- 2(1H)-one 484

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-heptanoylquinolin-2(1H)-one 485

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-octanoylquinolin-2(1H)-one 486

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-octanoyl-3,4-dihydroquinolin- 2(1H)-one 487

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-nonanoylquinolin-2(1H)-one 488

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-decanoylquinolin-2(1H)-one 489

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-undecanoylquinolin-2(1H)- one 490

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-dodecanoylquinolin-2(1H)- one 491

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-tridecanoylquinolin-2(1H)-one 492

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-tetradecanoylquinolin-2(1H)- one 493

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-pentadecanoylquinolin-2(1H)- one 494

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-palmitoylquinolin-2(1H)-one 495

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-heptadecanoylquinolin-2(1H)- one 496

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy-1-stearoylquinolin-2(1H)-one 497

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-nonadecanoylquinolin-2(1H)- one 498

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-icosanoylquinolin-2(1H)-one 499

7-4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-henicosanoylquinolin-2(1H)- one 500

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-docosanoylquinolin-2(1H)- one 501

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-tricosanoylquinolin-2(1H)-one 502

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-tetracosanoylquinolin-2(1H)- one 503

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2-methylbutanoyl)quinolin- 2(1H)-one 504

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-isobutyrylquinolin-2(1H)-one 505

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-isobutyryl-3,4- dihydroquinolin-2(1H)-one 506

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2-methylpentanoy)quinolin- 2(1H)-one 507

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2-methylhexanoyl)quinolin- 2(1H)-one 508

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (2,2-dimethylhexanoyl)quinolin- 2(1H)-one 509

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (2,2-dimethyloctanoyl)quinolin- 2(1H)-one 510

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2,2-dimethyloctanoyl)-3,4- dihydroquinolin-2(1H)-one 511

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (2,2-dimethyldecanoyl)quinolin- 2(1H)-one 512

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2-phenylacetyl)quinolin-2(1H)- one 513

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-benzoylquinolin-2(1H)-one 514

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-benzoyl-3,4-dihydroquinolin- 2(1H)-one 515

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(cyclobutanecarbonyl)quinolin- 2(1H)-one 516

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(cyclopentanecarbonyl)quinolin- 2(1H)-one 517

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(cyclonexanecarbonyl)quinolin- 2(1H)-one 518

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(cycloheptanecarbonyl)quinolin- 2(1H)-one 519

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-pivaloylquinolin-2(1H)-one 520

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2-hydroxyacetyl)quinolin-2(1H)- one 521

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2-hydroxyacetyl)-3,4- dihydroquinolin-2(1H)-one 522

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(4Z,7Z,10Z,13Z,16Z,19Z)- docosa-4,7,10,13,16,19-hexaenoylquinolin-2(1H)-one 523

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(9Z,12Z,15Z)-octadeca- 9,12,15-trienoylquinolin- 2(1H)-one 524

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(5Z,8Z,11Z,14Z,17Z)- henicosa-5,8,11,14,17- pentaenoylquinolin-2(1H)-one525

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(6Z,9Z,12Z,15Z)-octadeca- 6,9,12,15-tetraenoylquinolin- 2(1H)-one 526

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(7Z,10Z,13Z,16Z,19Z)- docosa-7,10,13,16,19- pentaenoylquinolin-2(1H)-one527

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(4Z,7Z,10Z,13Z,16Z)- docosa-4,7,10,13,16- pentaenoylquinolin-2(1H)-one528

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(4Z,7Z,10Z,13Z,16Z,19Z)- docosa-4,7,10,13,16,19-hexaenoylquinolin-2(1H)-one 529

2-amino-N-(2-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-2- oxoethyl)acetamide 530

2-amino-N-(2-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-2- oxoethyl)propanamide 531

2-amino-N-(2-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-2- oxoethyl)-3- methylbutanamide 532

2-amino-N-(2-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-2- oxoethyl)-4- methylpentanamide 533

N-(4-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-4- oxobutyl)acetamide 534

N-(4-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)-4- oxobutyl)acetamide 535

N-(4-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-4- oxobutyl)heptanamide 536

1-(2-aminoacetyl)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one 537

1-(2-aminopropanoyl)-7-(4- (4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one 538

1-(2-amino-4- methylpentanoyl)-7-(4-(4- (benzo[b]thiophen-4-yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one 539

2-amino-N-(2-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)-2- oxoethyl)acetamide 540

2-amino-N-(1-(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxaquinolin-1(2H)-yl)-3- methyl-1-oxobutan-2- yl)acetamide 541

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(pyrrolidine-2- carbonyl)quinolin-2(1H)-one 542

1-(1-(2- aminoacetyl)pyrrolidine-2- carbonyl)-7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one 543

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2-methoxyethoxy)acetyl)quinolin- 2(1H)one 544

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2-(2-methoxyethoxy)acetyl)- 3,4-dihydroquinolin-2(1H)- one 545

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(2- (2-(2-methoxyethoxy)ethoxy)acetyl) quinolin-2(1H)-one 546

methyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 547

methyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline- 1(2H)-carboxylate 548

ethyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 549

propyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 550

propyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline- 1(2H)-carboxylate 551

isobutyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 552

butyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 553

penty 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 554

pentyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline- 1(2H)-carboxylate 555

hexyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 556

isopentyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 557

isopropyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 558

isopropyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline- 1(2H)-carboxylate 559

cyclohexyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 560

cyclohexyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline- 1(2H)-carboxylate 561

heptyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 562

heptyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline- 1(2H)-carboxylate 563

octyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 564

nonyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 565

decyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 566

undecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 567

undecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoiine- 1(2H)-carboxylate 568

dodecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 569

tridecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 570

tetradecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 571

pentadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 572

hexadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 573

heptadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 574

octadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 575

nonadecyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 576

icosyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 577

henicosyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 578

docosyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 579

benzyl 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)- carboxylate 580

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-benzyl-2-oxoquinoline-1(2H)- carboxamide 581

calcium 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl phosphate 582

calcium 7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl phosphate 583

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-methyl-2-oxoquinoline-1(2H)- carboxamide 584

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-methyl-2-oxo-3,4- dihydroquinoline-1(2H)- carboxamide 585

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-ethyl-2-oxoquinoline-1(2H)- carboxamide 586

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-N-propylquinoline-1(2H)- carboxamide 587

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-butyl-2-oxoquinoline-1(2H)- carboxamide 588

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-N-pentylquinoline-1(2H)- carboxamide 589

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-hexyl-2-oxoquinoline-1(2H)- carboxamide 590

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-heptyl-2-oxoquinoline-1(2H)- carboxamide 591

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-heptyl-2-oxo-3,4- dihydroquinoline-1(2H)- carboxamide 592

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-octyl-2-oxoquinoline-1(2H)- carboxamide 593

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-nonyl-2-oxoquinoline-1(2H)- carboxamide 594

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-decyl-2-oxoquinoline-1(2H)- carboxamide 595

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-(2-hydroxyethyl)-2- oxoquinoline-1(2H)- carboxamide 596

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-dimethyl-2-oxoquinoline- 1(2H)-carboxamide 597

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-dimethyl-2-oxo-3,4- dihydroquinoline-1(2H)- carboxamide 598

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-diethyl-2-oxoquinoline-1(2H)- carboxamide 599

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-N,N-dipropylquinoline- 1(2H)-carboxamide 600

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-dibutyl-2-oxoquinoline-1(2H)- carboxamide 601

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-N,N-dipentylquinoline- 1(2H)-carboxamide 602

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-dihexyl-2-oxoquinoline-1(2H)- carboxamide 603

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-diheptyl-2-oxoquinoline- 1(2H)-carboxamide 604

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-diheptyl-2-oxo-3,4- dihydroquinoline-1(2H)- carboxamide 605

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-dinonyl-2-oxoquinoline-1(2Hy carboxamide 606

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2- oxo-N,N-ditetradecylquinoline-1(2H)- carboxamide 607

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-methyl-2-oxo-N- tetradecylquinoline-1(2H)- carboxamide 608

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N-methyl-N-nonyl-2- oxoquinoline-1(2H)- carboxamide 609

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1- (morpholine-4-carbonyl)quinolin-2(1H)-one 610

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(morpholine-4-carbonyl)-3,4- dihydroquinolin-2(1H)-one 611

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-bis(2-hydroxyethyl)-2- oxoquinoline-1(2H)- carboxamide 612

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-N,N-dibenzyl-2-oxoquinoline- 1(2H)-carboxamide 613

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(4-methylpiperazine-1- carbonyl)quinolin-2(1H)-one 614

1-(1,4′-bipiperidine-1′- carbonyl)-7-(4-(4- (benzo[b]thiophen-4-yl)piperazin-1- yl)butoxy)quinolin-2(1H)-one 615

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-1-(cyclopropanecarbony)quinolin- 2(1H)-one 616

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylpropionate 617

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylbutyrate 618

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylpentanoate 619

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylhexanoate 620

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylheptanoate 621

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloctanoate 622

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylnonanoate 623

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldecanoate 624

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylundecanoate 625

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yltridecanoate 626

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yltetradecanoate 627

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin4- yl)butoxy)quinolin-2-ylpentadecanoate 628

7-(4-(4- benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinoiin-2-ylpalmitate 629

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylheptadecanoate 630

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylstearate 631

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylicosanoate 632

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl2,2- dimethyltetradecanoate 633

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylpivalate 634

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl2,2- dimethylbutanoate 635

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylisobutyrate 636

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 2-hydrontacetate 637

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylcyclopropanecarboxylate 638

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylcyclobutanecarboxylate 639

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylcyclopentanecarboxylate 640

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylbenzoate 641

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 2-phenylacetate 642

(9Z,12Z,15Z)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl octadeca-9,12,15-trienoate 643

(5Z,8Z,11Z,14Z,17Z)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl henicosa-5,8,11,14,17- pentaenoate 644

(4Z,7Z,10Z,13Z,16Z,19Z)-7- (4-(4-(benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl docosa-4,7,10,13,16,19- hexaenoate 645

(6Z,9Z,12Z,15Z)-7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl octadeca-6,9,12,15- tetraenoate 646

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylmethyl carbonate 647

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylethyl carbonate 648

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylbutyl carbonate 649

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylpentyl carbonate 650

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylcyclohexyl carbonate 651

7-(4-(4-(benzo[bjthiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 2-methoxyethyl carbonate 652

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldiethyl phosphate 653

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylmethylcarbamate 654

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylethylcarbamate 655

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylpropylcarbamate 656

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylbutylcarbamate 657

7-(4-(4-(benzo[b]thiophen4- yl)piperazin-1- yl)butoxy)quinolin-2-ylpentylcarbamate 658

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylhexylcarbamate 659

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloctylcarbamate 660

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldecylcarbamate 661

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldodecylcarbamate 662

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yltetradecylcarbamate 663

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylhexadecylcarbamate 664

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldimethylcarbamate 665

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldipropylcarbamate 666

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldiisobutylcarbamate 667

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldibutylcarbamate 668

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldihexylcarbamate 669

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldioctylcarbamate 670

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldidecylcarbamate 671

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldidodecylcarbamate 672

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylditetradecylcarbamate 673

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yldihexadecylcarbamate 674

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylbis(2- hydroxyethyl)carbamate 675

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-ylpiperidine-1-carboxylate 676

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl 4-methylpiperazine-1- carboxylate 677

7-(4-(4-(benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yl1,4′- bipiperidine-1′-carboxylate 678

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1- (propionyloxymethyl)piperazin- 1-ium chloride 679

4-(benzo[b]thiophen-4-yl)-1- (butyryloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride 680

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1- (pentanoyloxymethyl)piperazin- 1-ium chloride 681

4-(benzo[b]thiophen-4-yl)-1- (hexanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride 682

4-(benzo[b]thiophen-4-yl)-1- (heptanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride 683

4-(benzo[b]thiophen-4-yl)-1- (octanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride 684

4-(benzo[b]thiophen-4-yl)-1- (nonanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride 685

4-(benzo[b]thiophen-4-yl)-1- (decanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride 686

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1- (undecanoyloxymethyl)pipera- zin-1-ium iodide 687

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1- (tetradecanoyloxymethyl)piper- azin-1-ium iodide 688

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1- (palmitoyloxymethyl)piperazin- 1-ium iodide 689

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1- (stearoyloxymethyl)piperazin- 1-ium iodide 690

4-(benzo[b]thiophen-4-yl)-1- (icosanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide 691

4-(benzo[b]thiophen-4-yl)-1- (docosanoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide 692

4-(benzo[b]thiophen-4-yl)-1- (cyclopentanecarbonyloxy-methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-iumiodide 693

4-(benzo[b]thiophen-4-yl)-1- (cyclohexanecarbonyloxy-methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-iumiodide 694

4-(benzo[b]thiophen-4-yl)-1- isobutyryloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride 695

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1-((2- propylpentanoyloxy)methyl)pi- perazin-1-ium iodide696

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1-((2- pentylheptanoyloxy)methyl)pi- perazin-1-ium iodide697

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1- (pivaloyloxymethyl)piperazin- 1-ium chloride 698

4-(benzo[b]thiophen-4-yl)-1- ((2,2- dimethylbutanoyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide699

4-(benzo[b]thiophen-4-yl)-1- ((2,2- dimethylpentanoyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide700

4-(benzo[b]thiophen-4-yl)-1- ((2,2- dimethylhexanoyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide701

4-(benzo[b]thiophen-4-yl)-1- ((2,2- dimethyltetradecanoyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-iumiodide 702

4-(benzo[b]thiophen-4-yl)-1- ((1- methylcyclohexanecarbonyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-iumiodide 703

4-(benzo[b]thiophen-4-yl)-1 ((hexylcarbamoyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide704

4-(benzo[b]thiophen-4-yl)-1- ((diethylcarbamoyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide705

4-(benzo[b]thiophen-4-yl)-1- ((dibenzylcarbamoyloxy)meth-yl)-1-(4-(2-oxo-1,2 dihydroquinolin-7- yloxy)butyl)piperazin-1-iumiodide 706

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1-((piperidine- 1- carbonyloxy)methyl)piperazin- 1-iumiodide 707

4-(benzo[b]thiophen-4-yl)-1- ((ethoxycarbonyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride708

4-(benzo[b]thiophen-4-yl)-1- ((cyclohexyloxycarbonyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-iumchloride 709

4-(benzo[b]thiophen-4-yl)-1- ((hexyloxycarbonyloxy)methyl)-1-(4-(2-oxo-1,2- dihydroquinolin-7- yloxy)butyl)piperazin-1-ium iodide710

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1-(((pentan-3- yloxy)carbonyloxy)methyl)pi- perazin-1-iumiodide 711

4-(benzo[b]thiophen-4-yl)-1- (benzoyloxymethyl)-1-(4-(2-oxo-1,2-dihydroquinolin-7- yloxy)butyl)piperazin-1-ium chloride 712

4-(benzo[b]thiophen-4-yl)-1- (4-(2-oxo-1,2-dihydroquinolin-7-yloxy)butyl)-1-((2- phenylacetoxy)methyl)pipera- zin-1-ium chloride713

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) succinate 714

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) succinate 715

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) glutarate 716

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-34-dihydroquinolin- 1(2H)-yl)methyl) glutarate 717

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) adipate 718

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) adipate 719

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) heptanedioate 720

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) heptanedioate 721

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) octanedioate 722

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) octanedioate- 723

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) decanedioate 724

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) decanedioate 725

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) dodecanedioate 726

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) dodecanedioate 727

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) tetradecanedioate 728

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) tetradecanedioate 729

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) hexadecanedioate 730

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) hexadecanedioate 731

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) octadecanedioate 732

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) octadecanedioate 733

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) icosanedioate 734

bis((7-(4-(4- (benzo[b]thiophen--4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) icosanedioate 735

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl) docosanedioate 736

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin- 1(2H)-yl)methyl) docosanedioate 737

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) succinate 738

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) glutarate 739

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) adipate 740

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) heptanedioate 741

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) octanedioate 742

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-y(oxy)methyl) decanedioate 743

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) dodecanedioate 744

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) tetradecanedioate 745

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) hexadecanedioate 746

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) octadecanedioate 747

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl)icosanedioate 748

bis((7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1- yl)butoxy)quinolin-2-yloxy)methyl) docosanedioate 749

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) succinate 750

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) glutarate 751

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) adipate 752

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) heptanedioate 753

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) octanedioate 754

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) decanedioate 755

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) dodecanedioate 756

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) tetradecanedioate 757

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) hexadecanedioate 758

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) octadecanedioate 759

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) icosanedioate 760

bis(7-(4-(4- (benzo[b]thiophen-4- yl)piperazin-1-yl)butoxy)quinolin-2-yl) docosanedioate

Example A: Synthesis of deuteride of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneA-1: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-oneSynthesis Method 1 Step 1: Synthesis of2-benzyloxy-7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)quinoline

To a mixture of 2-benzyloxy-7-hydroxy quinoline (2.52 g) and potassiumcarbonate (1.67 g) in dimethylformamide (25 ml) was added1,4-dibromobutane-d₈ (99.6 atom % D: 2.4 ml), and the mixture wasstirred at room temperature overnight. To the reaction mixture was addedwater, ethyl acetate, the insoluble material was filtered off, and thefiltrate was partitioned, washed with water, and dried over sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=10:0→9:1) to give2-benzyloxy-7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)quinoline (3.14 g).2-benzyloxy-7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)quinoline white powder,¹H-NMR (CDCl₃) δ: 5.52 (2H, s), 6.81 (1H, d, J=8.7 Hz), 7.02 (1H, dd,J=8.8, 2.5 Hz), 7.21 (1H, d, J=2.5 Hz), 7.29-7.47 (3H, m), 7.49-7.56(2H, m), 7.60 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=8.7 Hz)

Step 2: Synthesis of2-benzyloxy-7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]quinoline

A mixture of 2-benzyloxy-7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)quinoline(3.14 g), 1-benzothiophene-4-piperazine hydrochloride (2.43 g), sodiumiodide (1.31 g) and potassium carbonate (2.64 g) in dimethylformamide(60 ml) was stirred at 80° C. for 5 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, washed withwater, and dried over sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=7:3-+5:5) to give2-benzyloxy-7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]quinoline(3.73 g).2-benzyloxy-7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]quinoline:pale-yellow amorphous solid, ¹H-NMR (CDCl₃) δ: 2.64-2.83 (4H, m),3.14-3.25 (4H, m), 5.53 (2H, s), 6.81 (1H, d, J=8.8 Hz), 6.89 (1H, d,J=7.6 Hz), 7.03-7.08 (1H, m), 7.25-7.49 (7H, m), 7.50-7.63 (4H, m), 7.91(1H, d, J=8.8 Hz)

Step 3: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one

A mixture of2-benzyloxy-7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]quinoline(3.73 g) and 1N hydrochloric acid (35.1 ml) in tetrahydrofuran (60 ml)was stirred at 60° C. for 4 hr, and ice-cooled. Ice water was added, andthe mixture was stirred. The precipitated solid was collected byfiltration, washed with water and dried under reduced pressure. To amixture of the obtained powder in ethanol (70 ml) was added underice-cooling 1N sodium hydroxide to basify the mixture. The solvent wasevaporated under reduced pressure and the residue was washed with water,and recrystallized from a mixture of ethanol and water to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one(2.29 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one:white powder, ¹H-NMR (DMSO-d₆) δ: 2.54-2.67 (4H, m), 2.91-3.15 (4H, m),6.29 (1H, d, J=9.5 Hz), 6.75-6.83 (2H, m), 6.88 (1H, d, J=7.6 Hz),7.21-7.30 (1H, m), 7.39 (1H, d, J=5.5 Hz), 7.50-7.66 (2H, m), 7.69 (1H,d, J=5.5 Hz), 7.80 (1H, d, J=9.5 Hz), 11.58 (1H, s)

Synthesis Method 2 Step 1: Synthesis of7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d)-1H-quinolin-2-one

To a mixture of 7-hydroxy-1H-quinolin-2-one [70500-72-0] (0.72 g) andpotassium carbonate (0.68 g) in dimethylformamide (20 ml) was added1,4-dibromobutane-d₈ (99.6 atom % D: 3 g), and the mixture was stirredat 50° C. for 5 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate, washed with water, and driedover sodium sulfate. The solvent was evaporated under reduced pressureand the residue was purified by silica gel column chromatography(dichloromethane:methanol=100:1) to give7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one (1.1 g).

7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one: white powderlike, ¹H-NMR (CDCl₃) δ: 6.56 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 7.45(1H, d, J=8.6 Hz), 7.74 (1H, d, J=9.4 Hz), 12.33 (1H, brs).

Step 2: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one

A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one (0.4g), 1-benzothiophene-4-piperazine hydrochloride (0.37 g), potassiumcarbonate (0.45 g) and dimethylformamide (20 ml) was stirred at 60° C.for 6 hr. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate, washed with water, and dried over sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography(dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one(0.3 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-onesame as that synthesized in synthesis method 1 was obtained.

white powder m.p. 177-179° C. (recrystallized from EtOH)

A-2: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-oneStep 1: Synthesis of tert-butyl4-(benzo[b]thiophen-4-yl)piperazine-2,2,3,3,5,5,6,6-d₈-1-carboxylate

A mixture of 4-bromo-benzo[b]thiophene [5118-13-8] (0.55 g), tert-butyl1-piperazine-2,2,3,3,5,5,6,6-d₈-carboxylate (98.3 atom % D:0.5 g),sodium t-butoxide (0.25 g), (R)-(+)-BINAP (30 mg),tris(dibenzylideneacetone)dipalladium(0) (30 mg) and toluene (20 ml) washeated under reflux under an argon atmosphere for 3 hr. Water was pouredinto the reaction mixture, and the mixture was extracted with ethylacetate, washed with water, and dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (ethylacetate:n-hexane=1:100) to give tert-butyl4-(benzo[b]thiophen-4-yl)piperazine-2,2,3,3,5,5,6,6-d₈-1-carboxylate(0.41 g).

tert-butyl4-(benzo[b]thiophen-4-yl)piperazine-2,2,3,3,5,5,6,6-d₈-1-carboxylate

yellow powder

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.03-3.09 (0.06H, br), 3.59-3.65 (0.06H,br), 6.87 (1H, dd, J=0.8, 7.7 Hz), 7.28 (1H, t, J=7.8 Hz), 7.41 (2H, s),7.57 (1H, d, J=8.0 Hz).

Confirmed by ¹H-NMR (CDCl₃): at least 98 atom % D.

Step 2: Synthesis of1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d₈

To a solution of tert-butyl4-(benzo[b]thiophen-4-yl)piperazine-2,2,3,3,5,5,6,6-d₈-1-carboxylate(0.57 g) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml)and the mixture was stirred at room temperature for 3 hr. Water waspoured into the reaction mixture, alkalified with aqueous sodiumhydroxide solution, and the mixture was extracted with dichloromethane,washed with water, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (basic silica gel, ethylacetate:methanol=20:1) to give1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-de (0.31 g).

1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d₈: oil brown

¹H-NMR (CDCl₃) δ: 3.06-3.10 (0.13H, br), 6.88 (1H, dd, J=0.8, 7.6 Hz),7.27 (1H, t, J=7.8 Hz), 7.38 (1H, d, J=5.4 Hz), 7.42 (1H, dd, J=0.7, 5.5Hz), 7.54 (1H, d, J=8.1 Hz).

Confirmed by ¹H-NMR (CDCl₃): at least 98 atom % D.

Step 3: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one

A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one (633mg) obtained in Example A-1, synthesis method 2, step 1,l-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-de (471 mg) obtainedin this Example, step 2, potassium carbonate (374 mg) anddimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one(0.45 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one:yellow powder m.p. 176-178° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ: 2.64-2.72 (0.06H, m), 3.02-3.20 (0.06H, m), 6.55 (1H,d, J=9.4 Hz), 6.79-6.86 (2H, m), 6.89 (1H, dd, J=0.7, 7.6 Hz), 7.26 (1H,t, J=7.8 Hz), 7.36-7.46 (3H, m), 7.54 (1H, d, J=8.0 Hz), 7.72 (1H, d,J=9.4 Hz), 12.34 (1H, brs).

A-3: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy]-1H-quinolin-2-one

A mixture of 7-(4-chlorobutoxy)-1H-quinolin-2-one (340 mg),1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-de (310 mg) obtainedin Example A-2, step 2, sodium iodide (220 mg), potassium carbonate (240mg) and dimethylformamide (10 ml) was stirred at 60° C. for 6 hr. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate, washed with water, and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography(dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy]-1H-quinolin-2-one(0.31 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy]-1H-quinolin-2-one:yellow powder m.p. 175.5-177° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ: 1.70-1.84 (2H, m), 1.84-1.96 (2H, m), 2.54 (2H, t,J=7.5 Hz), 2.66-2.72 (0.06H, m), 3.14-3.18 (0.06H, m), 4.12 (2H, t,J=6.2 Hz), 6.54 (1H, d, J=9.4 Hz), 6.79-6.86 (2H, m), 6.89 (1H, dd,J=0.6, 7.6 Hz), 7.26 (1H, t, J=7.9 Hz), 7.36-7.48 (3H, m), 7.54 (1H, d,J=8.0 Hz), 7.72 (1H, d, J=9.4 Hz), 12.27 (1H, brs).

A-4: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅Step 1: Synthesis of 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d₅

To a mixture of 7-hydroxy-1H-quinolin-2-one-3,4,5,6,8-d₅ (99 atom % D: 3g) obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485.; Bull.Chem. Soc. Jpn. 2008, 81, 278.) of 7-hydroxy-1H-quinolin-2-one[70500-72-0] and potassium carbonate (3 g) in dimethylformamide (120 ml)was added 1,4-dibromobutane (6.5 ml), and the mixture was stirred at 50°C. for 4 hr. Water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate, washed with water, and dried oversodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography(dichloromethane:methanol=100:1) to give7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d₅ (3.45 g).

7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d₅: white powder like

¹H-NMR (CDCl₃) δ ppm: 1.94-2.05 (2H, m), 2.05-2.15 (2H, m), 3.51 (2H, t,J=6.5 Hz), 4.10 (2H, t, J=6.0 Hz), 6.55 (0.01H, s), 6.79-6.81 (2H, m),7.52 (0.008H, s), 7.73 (0.008H, s), 11.89 (1H, brs).

Step 2: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅

A mixture of 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d₅(0.6 g),1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-de (0.5 g), potassiumcarbonate (360 mg) and dimethylformamide (20 ml) was stirred at 60° C.for 5 hr. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate, washed with water, and dried over sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography(dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅(0.45 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₅)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅:white powder m.p. 175.5-177.5° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ ppm: 1.70-1.84 (2H, m), 1.80-1.96 (2H, m), 2.54 (2H, t,J=7.4 Hz), 2.66-2.72 (<0.07H, br), 3.14-3.20 (<0.06H, br), 4.12 (2H, t,J=6.2 Hz), 6.54 (<0.008H, s), 6.82 (<0.025H, d, J=5.7 Hz), 6.89 (1H, dd,J=0.6, 7.7 Hz), 7.26 (1H, t, J=7.9 Hz), 7.38 (1H, d, J=5.5 Hz), 7.42(1H, d, J=5.9 Hz), 7.54 (1H, d, J=8.0 Hz), 7.72 (<0.01H, s), 12.10 (1H,brs).

A-5: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅

A mixture of 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d₅ (0.6 g)obtained in Example A-4, step 1, 1-benzothiophene-4-piperazinehydrochloride (0.56 g), potassium carbonate (690 mg) anddimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅(0.5g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅:white powder m.p. 177-179° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ ppm: 1.70-1.85 (2H, m), 1.85-1.95 (2H, m), 2.54 (2H, t,J=7.4 Hz), 2.66-2.82 (4H, br), 3.14-3.28 (4H, br), 4.08-4.12 (2H, m),6.54 (<0.01H, s), 6.83 (<0.02H, d, J=10.3 Hz), 6.89 (1H, d, J=7.7 Hz),7.26 (1H, t, J=7.8 Hz), 7.36 (1H, d, J=5.5 Hz), 7.42 (1H, dd, J=0.6, 5.5Hz), 7.54 (1H, d, J=8.0 Hz), 7.72 (<0.01H, s), 12.24 (1H, brs).

A-6: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅

A mixture of 7-(4-bromobutoxy)-1H-quinolin-2-one-3,4,5,6,8-d₅ (0.6 g)obtained in Example A-4, step 1,1-benzo[b]thiophen-4-yl-5,7-d₂-piperazine hydrochloride (0.56 g)obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485.; Bull.Chem. Soc. Jpn. 2008, 81, 278.) of 1-benzothiophene-4-piperazinehydrochloride, potassium carbonate (690 mg) and dimethylformamide (20ml) was stirred at 60° C. for 5 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, washed withwater, and dried over sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography (dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d₅(0.42 g).

7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy]-1H-quinolin-2-one-3,4,5,6,8-d:white powder m.p. 176.5-178.5° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ ppm: 1.70-1.98 (4H, m), 2.54 (2H, t, J=7.4 Hz),2.66-2.80 (4H, br), 3.14-3.26 (4H, br), 4.12 (2H, t, J=6.1 Hz), 6.54(<0.01H, s), 6.83 (<0.02H, d, J=10.0 Hz), 6.89 (<0.01H, d, J=7.7 Hz),7.08 (<0.02H, m), 7.25-7.28 (1H, m), 7.38 (0.89H, d, J=5.5 Hz), 7.42(1H, d, J=5.5 Hz), 7.54 (0.06H, d, J=8.1 Hz), 7.72 (<0.01H, s), 12.23(1H, brs).

A-7: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅Step 1: Synthesis of7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one-3,4,5,6,8-d₅

To a mixture of 7-hydroxy-1H-quinolin-2-one-3,4,5,6,8-d₅ (99 atom % D:1.65 g) obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485.;Bull. Chem. Soc. Jpn. 2008, 81, 278.) of 7-hydroxy-1H-quinolin-2-one[70500-72-0] and potassium carbonate (1.51 g) in dimethylformamide (40ml) was added 1,4-dibromobutane-de (99.6 atom % D: 5.55 g), and themixture was stirred at 50° C. for 4 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, washed withwater, and dried over sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography (dichloromethane:methanol=100:1) to give7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d)-1H-quinolin-2-one-3,4,5,6,8-d₅ (1.1g).

7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one-3,4,5,6,8-d₅:white powder like, ¹H-NMR (CDCl₃) δ ppm: 6.55 (0.008H, s), 6.81 (0.021H,d, J=9.6 Hz), 7.45 (0.008H, s), 7.74 (0.008H, s), 12.28 (1H, brs).

Step 2: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅

A mixture of7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one-3,4,5,6,8-d₅ (0.5g) obtained in this Example, step 1, 1-benzothiophene-4-piperazinehydrochloride (0.45 g), potassium carbonate (0.56 g) anddimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅(0.24 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅:white powder m.p. 176-177.5° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ ppm: 2.60-2.84 (4H, br), 3.10-3.28 (4H, br), 6.54(<0.007H, s), 6.82 (<0.02H, d, J=6.0 Hz), 6.89 (1H, dd, J=0.5, 7.6 Hz),7.27 (1H, t, J=7.8 Hz), 7.38 (1H, d, J=5.6 Hz), 7.42 (1H, dd, J=0.5, 5.6Hz), 7.54 (1H, d, J=8.0 Hz), 7.72 (<0.009H, s), 12.13 (1H, brs).

A-8: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy]-1H-quinolin-2-one

A mixture of 7-(4-chlorobutoxy)-1H-quinolin-2-one (0.5 g),1-benzo[b]thiophen-4-yl-5,7-d₂-piperazine hydrochloride (0.56 g)obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485.; Bull.Chem. Soc. Jpn. 2008, 81, 278.) of 1-benzothiophene-4-piperazinehydrochloride, sodium iodide (0.33 g), potassium carbonate (690 mg) anddimethylformamide (20 ml) was stirred at 60° C. for 6 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(0.31 g).

7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy]-1H-quinolin-2-one:white powder m.p. 179.5-181.5° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ ppm: 1.68-1.84 (2H, m), 1.84-1.96 (2H, m), 2.54 (2H, t,J=7.4 Hz), 2.66-2.80 (4H, br), 3.16-3.26 (4H, br), 4.12 (2H, t, J=6.2Hz), 6.54 (1H, d, J=9.4 Hz), 6.78-6.86 (2H, m), 6.90 (<0.02H, d, J=7.7Hz), 7.25-7.28 (1H, m), 7.38 (0.82H, d, J=5.6 Hz), 7.40-7.48 (2H, m),7.54 (0.05H, d, J=8.6 Hz), 7.72 (1H, d, J=9.4 Hz), 12.09 (1H, brs).

A-9: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one

A mixture of 7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one (0.5g) obtained in Example A-1, synthesis method 2, step 1,1-benzo[b]thiophen-4-yl-5,7-d₂-piperazine hydrochloride (0.46 g)obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485.; Bull.Chem. Soc. Jpn. 2008, 81, 278.) of l-benzothiophene-4-piperazinehydrochloride, potassium carbonate (0.57 g) and dimethylformamide (20ml) was stirred at 50° C. for 6 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, washed withwater, and dried over sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography (dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one(0.35 g).

7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one:white powder m.p. 176.5-178.5° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ ppm: 2.66-2.80 (4H, br), 3.10-3.28 (4H, br), 6.55 (1H,d, J=9.4 Hz), 6.81 (1H, dd, J=2.4, 8.6 Hz), 6.85 (1H, d, J=2.3 Hz), 6.89(<0.04H, d, J=7.7 Hz), 7.24-7.28 (1H, m), 7.38 (0.85H, d, J=5.6 Hz),7.40-7.46 (2H, m), 7.54 (0.06H, dd, J=0.5, 8.0 Hz), 7.72 (1H, d, J=9.4Hz), 12.47 (1H, brs).

A-10: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅

A mixture of7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d)-1H-quinolin-2-one-3,4,5,6,8-d₅ (0.6g) obtained in Example A-7, step 1,1-benzo[b]thiophen-4-yl-piperazine-2,2,3,3,5,5,6,6-d₈ (0.57 g) obtainedin Example A-2, step 2, potassium carbonate (380 mg) anddimethylformamide (20 ml) was stirred at 60° C. for hr. Water was addedto the reaction mixture, and the mixture was extracted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (dichloromethane:methanol=30:1) to give7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₈)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅(0.45g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl-2,2,3,3,5,5,6,6-d₅)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅:white powder m.p. 175.5-177.5° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ ppm: 2.64-2.72 (<0.06H, br), 3.14-3.20 (<0.06H, br),6.54 (<0.01H, s), 6.80-6.86 (<0.04H, m), 6.89 (1H, dd, J=0.8, 7.6 Hz),7.26 (1H, t, J=7.9 Hz), 7.38 (1H, d, J=5.5 Hz), 7.41 (1H, dd, J=0.7, 5.6Hz), 7.54 (1H, d, J=8.0 Hz), 7.72 (<0.01H, s), 12.35 (1H, brs).

A-11: Synthesis of7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅

A mixture of7-(4-bromobutoxy-1,1,2,2,3,3,4,4-d₈)-1H-quinolin-2-one-3,4,5,6,8-d₅ (0.5g) obtained in Example A-7, step 1,1-benzo[b]thiophen-4-yl-5,7-d₂-piperazine hydrochloride (0.46 g)obtained by a deuteration reaction (Org. Lett. 2004, 6, 1485.; Bull.Chem. Soc. Jpn. 2008, 81, 278.) of 1-benzothiophene-4-piperazinehydrochloride, potassium carbonate (0.56 g) and dimethylformamide (20ml) was stirred at 50° C. for 6 hr. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, washed withwater, and dried over sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography (dichloromethane:methanol=30:1) to give7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinoline-2-one-3,4,5,6,8-d₅(0.34 g).

7-[4-(4-benzo[b]thiophen-4-yl-5,7-d₂-piperazin-1-yl)-butoxy-1,1,2,2,3,3,4,4-d₈]-1H-quinolin-2-one-3,4,5,6,8-d₅:white powder m.p. 175.5-177.5° C. (recrystallized from EtOH)

¹H-NMR (CDCl₃) δ ppm: 2.66-2.80 (4H, br), 3.14-3.26 (4H, br), 6.54(<0.01H, s), 6.83 (<0.02H, d, J=11.2 Hz), 6.89 (<0.01H, d, J=7.6 Hz),7.06-7.10 (<0.02H, m), 7.25-7.28 (1H, m), 7.38 (0.86H, d, J=5.6 Hz),7.42 (1H, d, J=5.6 Hz), 7.54 (<0.05H, dd, J=0.6, 8.0 Hz), 7.72 (<0.01H,s), 12.28 (1H, brs).

Example B: Synthesis of salt of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one

Phosphate:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(15 g) in dichloromethane (100 ml) and methanol (100 ml) was warmed to60° C., dissolved, and phosphoric acid (4.39 g) was added at roomtemperature. The precipitated crystals were collected by filtration, anddried to give7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onephosphate (17.9 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-onephosphate (17.5 g) was recrystallized from ethanol (550 ml) and water(550 ml) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onephosphate (14.4 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onephosphate:colorless crystals:m.p. 226-228° C. (recrystallized fromEtOH—H₂O)

¹H-NMR (DMSO-d₆) δ ppm: 1.66-1.76 (2H, m), 1.76-1.86 (2H, m), 2.63 (2H,t, J=7.0 Hz), 2.76-2.86 (4H, br), 3.08-3.18 (4H, br), 4.07 (2H, t, J=6.2Hz), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.90 (1H, d, J=7.4 Hz),7.28 (1H, t, J=7.8 Hz), 7.42 (1H, d, J=5.5 Hz), 7.56 (1H, d, J=9.4 Hz),7.63 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz),11.2-12.2 (1H, br).

DL-Malate:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(15 g) in dichloromethane (100 ml) and methanol (100 ml) was warmed to60° C., dissolved, and DL-malic acid (5.11 g) dissolved in water (10 ml)was added at room temperature. The precipitated crystals were collectedby filtration, and dried to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneDL-malate (20 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-oneDL-malate (20 g) was recrystallized from ethanol (350 ml) and water (50ml) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneDL-malate (14.5 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneDL-malate: colorless crystal: m.p. 136-139° C. (recrystallized fromEtOH—H₂O)

¹H-NMR (DMSO-d₈) δ ppm: 1.64-1.76 (2H, m), 1.76-1.86 (2H, m), 2.62 (2H,t, J=7.1 Hz), 2.74-2.86 (4H, br), 3.06-3.18 (4H, br), 4.06 (2H, t, J=6.0Hz), 4.21 (2H, s), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.90 (1H,d, J=7.4 Hz), 7.28 (1H, t, J=7.8 Hz), 7.42 (1H, d, J=5.5 Hz), 7.56 (1H,d, J=9.3 Hz), 7.63 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=5.5 Hz), 7.81 (1H,d, J=9.5 Hz), 11.59 (1H, brs).

L(4)-Tartrate:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(15 g) in dichloromethane (100 ml) and methanol (100 ml) was heated to60° C., dissolved, and L(4)-tartaric acid (5.72 g) dissolved in water(10 ml) was added at room temperature. The precipitated crystals werecollected by filtration, and dried to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneL(+)-tartrate (19.3 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneL(+)-tartrate (19.3 g) was recrystallized from ethanol (700 ml) andwater (250 ml) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneL(+)-tartrate (16.5 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneL(+)-tartrate: colorless crystal: m.p. 198-203° C. (recrystallized fromEtOH—H₂O)

¹H-NMR (DMSO-d₆) δ ppm: 1.64-1.76 (2H, m), 1.76-1.86 (2H, m), 2.41 (1H,dd, J=6.7, 15.6 Hz), 2.59 (1H, dd, J=6.4, 15.6 Hz), 2.66 (2H, t, J=7.2Hz), 2.78-2.88 (4H, br), 3.06-3.18 (4H, br), 4.07 (2H, t, J=6.2 Hz),4.16 (1H, t, J=6.5 Hz), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.90(1H, d, J=7.2 Hz), 7.29 (1H, t, J=7.8 Hz), 7.43 (1H, dd, J=0.6, 5.5 Hz),7.56 (1H, d, J=9.3 Hz), 7.63 (1H, d, J=8.0 Hz), 7.71 (1H, d, J=5.5 Hz),7.81 (1H, d, J=9.5 Hz), 11.59 (1H, brs).

Oxalate:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(3 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60°C., dissolved, and oxalic acid (0.69 g) dissolved in methanol (5 ml) wasadded at room temperature. The precipitated crystals were collected byfiltration, and dried to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneoxalate (3.3 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-oneoxalate (1 g) was recrystallized from ethanol (20 ml) and water (20 ml)to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneoxalate (0.8 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-oneoxalate: colorless crystal: m.p. 126.5-128° C. (recrystallized fromEtOH—H₂O)

¹H-NMR (DMSO-d₆) δ ppm: 1.78-1.90 (4H, br), 3.06-3.14 (2H, br),3.24-3.36 (4H, br), 3.62-4.24 (6H, br), 6.31 (1H, d, J=9.4 Hz),6.78-6.86 (2H, m), 6.95 (1H, d, J=7.4 Hz), 7.31 (1H, t, J=7.9 Hz), 7.48(1H, dd, J=0.4, 5.6 Hz), 7.57 (1H, d, J=9.4 Hz), 7.69 (1H, d, J=8.1 Hz),7.75 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 11.62 (1H, brs).

succinate:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(2 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60°C., dissolved, and succinic acid (0.6 g) dissolved in methanol-water wasadded at room temperature. The precipitated crystals were collected byfiltration, and dried to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onesuccinate (2.4 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onesuccinate (1 g) was recrystallized from ethanol (20 ml) and water (8 ml)to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onesuccinate (0.74 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onesuccinate: colorless crystal: m.p. 158.5-160° C. (recrystallized fromEtOH—H₂O)

¹H-NMR (DMSO-d₆) δ ppm: 1.60-1.70 (2H, m), 1.76-1.86 (2H, m), 2.41 (4H,s), 2.44-2.50 (2H, m), 2.60-2.70 (4H, br), 3.04-3.10 (4H, br), 4.06 (2H,t, J=6.4 Hz), 6.29 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.89 (1H, d,J=7.3 Hz), 7.27 (1H, t, J=7.8 Hz), 7.40 (1H, dd, J=0.4, 5.6 Hz), 7.56(1H, d, J=9.3 Hz), 7.61 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=5.5 Hz), 7.81(1H, d, J=9.5 Hz), 11.58 (1H, brs).

1/2 Succinate:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(2 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60°C., dissolved, and succinic acid (0.3 g) dissolved in methanol-water wasadded at room temperature. The precipitated crystals were collected byfiltration, and dried to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one1/2 succinate (1.84 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-one1/2 succinate (1 g) was recrystallized from ethanol (20 ml) and water (5ml) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-H-quinolin-2-one1/2 succinate (0.69 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one1/2 succinate: colorless crystal: m.p. 158-160° C. (recrystallized fromEtOH—H₂O)

¹H-NMR (DMSO-d₆) δ ppm: 1.60-1.70 (2H, m), 1.76-1.86 (2H, m), 2.41 (211,s), 2.47 (2H, t, J=7.2 Hz), 2.60-2.70 (4H, br), 3.02-3.10 (4H, br), 4.06(2H, t, J=6.4 Hz), 6.30 (1H, d, J=9.4 Hz), 6.78-6.84 (2H, m), 6.88 (1H,d, J=7.3 Hz), 7.28 (1H, t, J=7.8 Hz), 7.40 (1H, dd, J=0.4, 5.5 Hz), 7.56(1H, d, J=9.4 Hz), 7.61 (1H, d, J=7.6 Hz), 7.69 (1H, d, J=5.5 Hz), 7.80(1H, d, J=9.5 Hz), 11.59 (1H, brs).

Hydrobromide:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(2 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60°C., dissolved, and a solution of 47% hydrobromic acid (0.86 g) inmethanol was added at room temperature. The precipitated crystals werecollected by filtration, and dried to give7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onehydrobromide (2.2 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onehydrobromide (1 g) was recrystallized from ethanol (20 ml) and water (5ml) to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onehydrobromide (0.81 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onehydrobromide: colorless crystal: m.p. 223-228° C. (recrystallized fromEtOH—H₂O)

¹H-NMR (DMSO-d₆) δ ppm: 1.80-2.00 (4H, br), 3.06-3.20 (2H, m), 3.26-3.40(4H, br), 3.50-3.74 (4H, m), 4.09 (2H, t, J=5.4 Hz), 6.31 (1H, d, J=9.4Hz), 6.80-6.86 (2H, m), 6.99 (1H, d, J=7.6 Hz), 7.33 (1H, t, J=7.9 Hz),7.51 (1H, d, J=5.5 Hz), 7.59 (1H, d, J=9.2 Hz), 7.72 (1H, d, J=8.0 Hz),7.78 (1H, d, J=5.5 Hz), 7.82 (1H, d, J=9.5 Hz), 9.65 (1H, brs), 11.62(1H, s).

Malonate:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(2 g) in dichloromethane (20 ml) and methanol (20 ml) was warmed to 60°C., dissolved, and malonic acid(0.53 g) dissolved in methanol was addedat room temperature. The precipitated crystals were collected byfiltration, and dried to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onemalonate (2.4 g).

7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onemalonate (1 g) was recrystallized from ethanol (4 ml) and water (10 ml)to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-onemalonate (0.72 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-y)-butoxy]-1H-quinolin-2-onemalonate: colorless crystal: m.p. 134-136° C. (recrystallized fromEtOH—H₂O)

¹H-NMR (DMSO-d₆) δ ppm: 1.68-1.88 (4H, m), 2.82 (2H, brs), 2.92-3.08(6H, m), 3.12-3.22 (4H, br), 4.07 (2H, t, J=5.8 Hz), 6.30 (1H, d, J=9.4Hz), 6.78-6.84 (2H, m), 6.93 (1H, d, J=7.6 Hz), 7.30 (1H, t, J=7.8 Hz),7.45 (1H, d, J=5.5 Hz), 7.57 (1H, d, J=9.4 Hz), 7.66 (1H, d, J=8.1 Hz),7.73 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 11.60 (1H, brs).

1/2 Pamoate:

A suspension of7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one(1 g) in dimethylformamide (10 ml) and acetonitrile (10 ml) was warmedto give a solution, and pamoic acid (0.49 g) was added. The mixture waswarmed to 60° C., dissolved, and the mixture was stood at roomtemperature. Water was added, the suspended substances were collected byfiltration, and dried to give7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one1/2 pamoate (1.5 g).

7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one1/2 pamoate: yellow amorphous

¹H-NMR (DMSO-d₆) δ ppm: 1.78-1.92 (4H, m), 3.4-3.8 (10H, br), 4.05-4.12(2H, m), 4.71 (1H, s), 6.31 (1H, d, J=9.5 Hz), 6.78-6.84 (2H, m), 6.96(1H, d, J=7.6 Hz), 7.04 (1H, t, J=7.4 Hz), 7.13-7.19 (1H, m), 7.31 (1H,t, J=7.8 Hz), 7.49 (1H, d, J=5.5 Hz), 7.56 (1H, d, J=8.7 Hz), 7.69 (2H,d, J=8.0 Hz), 7.76 (1H, d, J=5.5 Hz), 7.81 (1H, d, J=9.5 Hz), 8.18 (1H,d, J=8.6 Hz), 8.25 (1H, s), 11.63 (1H, brs).

Experimental Example 1

Each of the Example compounds was examined for the solubility in oil(sesame oil, benzyl benzoate).

For the specific gravity of an oil, the following values were applied.

sesame oil (specific gravity: 0.914-0.921)benzyl benzoate (specific gravity: 1.123)

(Method)

Example compound is measured in a microtube and an oil (sesame oil, or,benzyl benzoate) in an amount to make the concentration 10 mg/0.1 ml isadded. After stirring, the solubility is evaluated by visualobservation. When the compound is not dissolved, the mixture is heated,and the solubility is evaluated after cooling.

The results are shown in Table 3 and Table 4. In the Tables, ◯ meanssoluble.

TABLE 3 Example No. Sesame oil Example 17  ∘ Example 21  ∘ Example 28  ∘Example 44  ∘ Example 45  ∘ Example 52  ∘ Example 57  ∘ Example 60  ∘Example 75  ∘ Example 76  ∘ Example 79  ∘ Example 134 ∘ Example 135 ∘Example 142 ∘ Example 144 ∘ Example 149 ∘ Example 150 ∘ Example 154 ∘Example 156 ∘ Example 158 ∘ Example 177 ∘ Example 179 ∘ Example 180 ∘Example 373 ∘ Example 379 ∘ Example 380 ∘ Example 381 ∘ Example 384 ∘

TABLE 4 Example No. benzyl benzoate Example 9   ∘ Example 10  ∘ Example11  ∘ Example 12  ∘ Example 13  ∘ Example 14  ∘ Example 15  ∘ Example16  ∘ Example 17  ∘ Example 18  ∘ Example 19  ∘ Example 20  ∘ Example21  ∘ Example 22  ∘ Example 23  ∘ Example 24  ∘ Example 25  ∘ Example26  ∘ Example 27  ∘ Example 28  ∘ Example 29  ∘ Example 30  ∘ Example31  ∘ Example 32  ∘ Example 33  ∘ Example 34  ∘ Example 35  ∘ Example36  ∘ Example 37  ∘ Example 38  ∘ Example 39  ∘ Example 40  ∘ Example41  ∘ Example 42  ∘ Example 43  ∘ Example 44  ∘ Example 45  ∘ Example46  ∘ Example 47  ∘ Example 48  ∘ Example 49  ∘ Example 50  ∘ Example51  ∘ Example 52  ∘ Example 53  ∘ Example 54  ∘ Example 55  ∘ Example56  ∘ Example 57  ∘ Example 58  ∘ Example 59  ∘ Example 60  ∘ Example61  ∘ Example 62  ∘ Example 63  ∘ Example 64  ∘ Example 65  ∘ Example67  ∘ Example 68  ∘ Example 69  ∘ Example 70  ∘ Example 71  ∘ Example72  ∘ Example 73  ∘ Example 74  ∘ Example 75  ∘ Example 76  ∘ Example77  ∘ Example 78  ∘ Example 79  ∘ Example 80  ∘ Example 81  ∘ Example82  ∘ Example 83  ∘ Example 84  ∘ Example 85  ∘ Example 86  ∘ Example87  ∘ Example 88  ∘ Example 89  ∘ Example 90  ∘ Example 91  ∘ Example92  ∘ Example 93  ∘ Example 94  ∘ Example 95  ∘ Example 96  ∘ Example97  ∘ Example 98  ∘ Example 99  ∘ Example 100 ∘ Example 101 ∘ Example102 ∘ Example 103 ∘ Example 104 ∘ Example 105 ∘ Example 106 ∘ Example107 ∘ Example 108 ∘ Example 109 ∘ Example 110 ∘ Example 111 ∘ Example112 ∘ Example 113 ∘ Example 114 ∘ Example 115 ∘ Example 116 ∘ Example117 ∘ Example 118 ∘ Example 119 ∘ Example 120 ∘ Example 121 ∘ Example122 ∘ Example 123 ∘ Example 124 ∘ Example 125 ∘ Example 126 ∘ Example127 ∘ Example 128 ∘ Example 129 ∘ Example 130 ∘ Example 131 ∘ Example132 ∘ Example 134 ∘ Example 135 ∘ Example 136 ∘ Example 137 ∘ Example139 ∘ Example 140 ∘ Example 141 ∘ Example 142 ∘ Example 143 ∘ Example144 ∘ Example 145 ∘ Example 146 ∘ Example 147 ∘ Example 148 ∘ Example149 ∘ Example 150 ∘ Example 151 ∘ Example 152 ∘ Example 153 ∘ Example154 ∘ Example 156 ∘ Example 158 ∘ Example 163 ∘ Example 165 ∘ Example168 ∘ Example 170 ∘ Example 175 ∘ Example 177 ∘ Example 179 ∘ Example180 ∘ Example 371 ∘ Example 372 ∘ Example 373 ∘ Example 379 ∘ Example380 ∘ Example 381 ∘ Example 382 ∘ Example 384 ∘

Experimental Example 2; Pharmacokinetics of Intramuscular Preparations

A suspended fine particle preparation used as a sustainable injectionrequires re-suspending before administration, and the particle surfacearea markedly affects the drug release profile. Thus, the particle sizeafter re-suspending needs to be strictly controlled, so that coagulationand the like will not occur.

On the other hand, since an oil-soluble preparation contains a drugcompletely dissolved therein, re-suspending before administration is notnecessary and, since the drug is released depending on the oil-waterdistribution coefficient, control of the particle size is not necessary.Furthermore, since sterilization by filtration, which has beenunattainable for suspended fine particle preparations, has becomepossible, a preparation can be prepared more conveniently.

Since the compound disclosed in patent document 1 shows low solubilityin an oil base material such as benzyl benzoate and the like, anoil-soluble preparation cannot be produced. When a soluble preparationis produced, an aqueous base material using a solubilizing agent such asCaptisol (Sulfobutylether-β-cyclodextrin) and the like needs to be used.In contrast, since the compound of the present invention shows highsolubility in an oil base material, an oil-soluble preparation can beproduced.

Thus, an oil-soluble preparation of the compound of the presentinvention and an water soluble preparation of the compound disclosed inpatent document 1 were prepared, intramuscularly administered to ratsand pharmacokinetics of these preparations were evaluated.

Animal

7-week-old male rats were purchased from CHARLES RIVER LABORATORIESJAPAN, INC, preliminarily bred and rats weighing 265.2 g-288.6 g wereused for the experiment. The experiment was performed under theconditions of no fasting, free access to water and feed, and thefollowing breeding environment. Rats per cage: 4, temperature: 23±2° C.,humidity: 60±10%, light-on time: 7:00-19:00

Production Method of Preparation

As the compound disclosed in patent document 1, used was7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one(control compound) disclosed in Example 1 that expresses desiredefficacy. A water-soluble preparation was obtained by dissolving thecontrol compound in aqueous 15% Captisol and 0.78% tartaric acidsolution to a concentration of 0.5%, and the pH was adjusted to 4.3 with5N aqueous sodium hydroxide solution.

An oil-soluble preparation was obtained by dissolving the compound ofthe present invention disclosed in Example 146 in benzyl benzoate to aconcentration of 15%, and adjusted.

Methods of Administration and Blood Sampling

Under isoflurane anesthesia, non-fasting male rats were intramuscularlyadministered at left leg region (about 4 mm depth) using a syringe with24G needle. The dose is as described below.

Test preparation 1: low dose of oil-soluble preparation of the compoundof the present invention: 25 mg/kg (based on control compound)Test preparation 2: high dose of oil-soluble preparation of the compoundof the present invention: 50 mg/kg (based on control compound)Test preparation 3: water-soluble preparation of control compound: 0.1mg/kg

The test preparation was administered to the rats. For test preparation3, about 0.3 mL each of blood samples were collected from the jugularvein 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr and 20 hr later. For testpreparations 1 and 2, about 0.3 mL each of blood samples were collectedfrom the jugular vein 6 hr, 1 day, 3 days, 7 days, 14 days, 21 days and28 days later. For collection of blood samples, a 1 mL syringe treatedwith EDTA-lithium fluoride-heparin was used. The collected blood waspreserved under ice-cooling, the plasma was rapidly separated bycentrifugation, and the concentration of the control compound wasquantified by LCMS. The pharmacokinetics parameters such as Cmax, Tmax,AUClast, AUCinf, t1/2 and the like were determined by WinNonlinProfessional Version 6.1 (model-independent method, Pharsightcorporation).

Results

The results are shown in FIG. 1 (blood concentration profile of controlcompound after administration of test preparations 1, 2 and 3) and Table5 (pharmacokinetics parameters of test preparations 1, 2 and 3).

TABLE 5 Cmax Tmax AUClast AUCinf t_(1/2) (μg/mL) (day) (μg · day/mL) (μg· day/mL) (day) Test preparation 1 0.0258 5.00 0.270 0.473 27.99 Testpreparation 2 0.0423 5.31 0.480 0.621 16.99 Test preparation 3 0.06290.01 0.003 0.003 0.05 Each parameter shows mean value (n = 4)

Discussion

In test preparation 3, the control compound disappeared immediatelyafter intramuscular administration. On the other hand, in testpreparations 1 and 2, the control compound showed a sustained bloodconcentration profile. Therefrom it was shown that the improvedsolubility of the compound of the present invention in an oily substratehas enabled the production of a dissolution preparation that shows bloodconcentration sustainability of the compound of patent document 1.

This application is based on application No. 61/532,393 filed in UnitedStates of America (filing date; Sep. 8, 2011), the content of which isincorporated hereinto by reference.

1. A heterocyclic compound represented by the formula (I)

wherein A is a lower alkylene group;

in the monocyclic heterocycle containing Q is

wherein R^(2′) is the following group

wherein Y^(1′) is a lower alkylene group, R^(3′) is (1) an alkyl group,(2) a cycloalkyl group optionally substituted by a lower alkyl group,(3) a phenyl group, (4) a phenyl lower alkyl group (5) a lower alkoxygroup, (6) a cycloalkyloxy group, (7) an amino group optionally having 1or 2 substituents selected from the group consisting of an alkyl groupand a phenyl lower alkyl group, or (8) a piperidyl group optionallyhaving a piperidyl group;

at the 3-position and the 4-position of the bicyclic heterocycleskeleton containing Z and W is —CH═CH— or

wherein R⁶ and R⁷ are the same or different and each is a hydrogen or alower alkyl group;—W

Z— is

wherein R¹ is a lower alkoxy lower alkoxy group, a phosphonooxy loweralkoxy group, a phenyl lower alkoxy lower alkoxy group, a phosphonooxygroup optionally having 1 or 2 lower alkyl groups, the following group

wherein R⁸ is (1) an alkyl group, (2) a hydroxy-substituted lower alkylgroup, (3) a cycloalkyl group, (4) a phenyl group, (5) a phenyl loweralkyl group, (6) an alkenyl group, (7) a lower alkoxy group, (8) acycloalkyloxy group, (9) a lower alkoxy lower alkoxy group, (10) anamino group optionally having 1 or 2 substituents selected from thegroup consisting of an alkyl group and a hydroxy-substituted lower alkylgroup, (11) a piperidyl group optionally having a piperidyl group, (12)a piperazinyl group optionally having a lower alkyl group, or (13) thefollowing group

wherein Aa is an alkylene group, and other symbols are as defined above,or the following group

wherein R⁹ is (1) an alkyl group, (2) a hydroxy-substituted lower alkylgroup, (3) a cycloalkyl group, (4) a phenyl group, (5) a phenyl loweralkyl group, (6) an alkenyl group, (7) a lower alkoxy group, (8) acycloalkyloxy group, (9) a lower alkoxy lower alkoxy group, (10) aphenyloxy group, (11) an amino group optionally having 1 or 2substituents selected from the group consisting of an alkyl group and ahydroxy-substituted lower alkyl group, (12) a piperidyl group optionallyhaving a piperidyl group, (13) a piperazinyl group optionally having alower alkyl group, or (14) the following group

wherein Ab is an alkylene group, and other symbols are as defined above;R² is a hydrogen or the following group

wherein Y¹ is a lower alkylene group optionally substituted by (1) alower alkoxycarbonyl group or (2) a lower alkyl group, Y² is a loweralkylene group, Y³ is a single bond or a lower alkylene group optionallysubstituted by a lower alkyl group, R³ is (1) an alkyl group, (2) ahalogen-substituted lower alkyl group, (3) an alkenyl group, (4) anamino lower alkyl group, (5) a cycloalkyl group, (6) a phenyl group, (7)a phenyl lower alkyl group, (8) a piperidyl group optionally having 1 or2 substituents selected from the group consisting of a lower alkyl groupand a piperidyl group, (9) a halogen-substituted piperidyl group, (10) amorpholinyl group, (11) a pyrrolidinyl group, (12) a tetrahydropyranylgroup, (13) a furyl group, (14) a thienyl group, (15) a pyridyl group,(16) a pyrimidinyl group, (17) a pyridazinyl group, (18) a benzofurylgroup, (19) a quinolyl group, (20) a lower alkoxycarbonyl lower alkylgroup, (21) a lower alkoxy lower alkoxy lower alkyl group, (22) a loweralkoxy lower alkoxy lower alkoxy lower alkyl group, (23) an amino groupoptionally having 1 or 2 substituents selected from the group consistingof an alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, alower alkenyl group, a halogen-substituted lower alkyl group, a loweralkoxy group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyllower alkyl group, a phenyl lower alkyl group, a phenyl lower alkoxygroup, a furyl lower alkyl group, a pyridyl lower alkyl group, ahydroxy-substituted lower alkyl group, (24) an amino lower alkyl groupoptionally having a lower alkylcarbonyl group, (25) a piperazinyl groupoptionally having a lower alkyl group, or (26) the following group

wherein Ac is an alkylene group, and other symbols are as defined above,R⁴ is (1) an alkyl group, (2) a phenyl group, (3) a phenyl lower alkylgroup, (4) a halogen-substituted lower alkyl group, or (5) a cycloalkylgroup, R⁵ is (1) a hydrogen, (2) a lower alkyl group, (3) ahalogen-substituted lower alkyl group, (4) a phenyl lower alkyl group,(5) a phenyl lower alkoxy lower alkyl group, (6) a tri-lower alkylsilylgroup, (7) a tetrahydropyranyl group, or (8) a phosphono group, R¹⁰ is(1) an alkyl group, (2) an alkenyl group, (3) a phenyl group, (4) aphenyl lower alkyl group, (5) a hydroxy-substituted lower alkyl group,(6) a cycloalkyl group, (7) an amino lower alkyl group optionally having1 or 2 substituents selected from the group consisting of an amino loweralkylcarbonyl group and a lower alkylcarbonyl group, (8) a pyrrolidinylgroup optionally having an amino lower alkylcarbonyl group, (9) analkoxy group, (10) a lower alkoxy lower alkoxy lower alkyl group, (11) alower alkoxy lower alkoxy lower alkoxy lower alkyl group, (12) a phenyllower alkoxy group, (13) an amino group optionally having 1 or 2substituents selected from the group consisting of an alkyl group, ahydroxy-substituted lower alkyl group and a phenyl lower alkyl group,(14) a morpholino group, (15) a piperazinyl group optionally having alower alkyl group, (16) a piperidyl group optionally having a piperidylgroup, or (17) a cycloalkyloxy group; provided when

then R² is not a hydrogen, or a salt thereof.
 2. The heterocycliccompound according to claim 1, which is represented by the formula (II)

wherein each symbol is as defined in claim 1, or a salt thereof.
 3. Theheterocyclic compound according to claim 1, which is represented by theformula (III)

wherein-Wa

Za- is

wherein R^(1a) is the following group

wherein R^(8a) is (1) an alkyl group, (2) a cycloalkyl group, (3) alower alkoxy group, (4) a cycloalkyloxy group, (5) a lower alkoxy loweralkoxy group, (6) an amino group optionally having 1 or 2 substituentsselected from the group consisting of an alkyl group and ahydroxy-substituted lower alkyl group, or (7) the following group

wherein Aa′ is an alkylene group, and other symbol is as defined inclaim 1, or the following group

wherein R^(9a) is (1) an alkyl group, (2) a hydroxy-substituted loweralkyl group, (3) a cycloalkyl group, (4) a lower alkoxy group, (5) acycloalkyloxy group, (6) a lower alkoxy lower alkoxy group, (7) aphenyloxy group, (8) an amino group optionally having 1 or 2substituents selected from the group consisting of an alkyl group, (9) apiperidyl group optionally having a piperidyl group, (10) a piperazinylgroup optionally having a lower alkyl group, or (11) the following group

wherein Ab′ is an alkylene group, and other symbol is as defined inclaim 1; R^(2a) is the following group

wherein Y^(1a) is a lower alkylene group, Y^(2a) is a lower alkylenegroup, R^(3a) is (1) an alkyl group, (2) a cycloalkyl group, (3) apiperidyl group optionally having 1 or 2 substituents selected from thegroup consisting of a lower alkyl group, (4) a tetrahydropyranyl group,(5) a lower alkoxycarbonyl lower alkyl group, (6) a lower alkoxy loweralkoxy lower alkyl group (7) an amino lower alkyl group optionallyhaving a lower alkylcarbonyl group, or (8) the following group

wherein Ac′ is an alkylene group, Y^(1a) is a lower alkylene group andother symbols are as defined in claim 1, R^(4a) is (1) an alkyl group,or (2) a cycloalkyl group; and A is a lower alkylene group, or a saltthereof.
 4. The heterocyclic compound according to claim 2, wherein R¹is the following group

wherein R^(8a′) is (1) an alkyl group, (2) a cycloalkyl group, (3) alower alkoxy group, (4) a cycloalkyloxy group, (5) a lower alkoxy loweralkoxy group, or (6) an amino group optionally having 1 or 2substituents selected from the group consisting of an alkyl group and ahydroxy-substituted lower alkyl group, or the following group

wherein R^(9a′) is (1) an alkyl group, (2) a hydroxy-substituted loweralkyl group, (3) a cycloalkyl group, (4) a lower alkoxy group, (5) acycloalkyloxy group, (6) a lower alkoxy lower alkoxy group, (7) aphenyloxy group, (8) an amino group optionally having 1 or 2substituents selected from the group consisting of an alkyl group, (9) apiperidyl group optionally having a piperidyl group, or (10) apiperazinyl group optionally having a lower alkyl group; R² is thefollowing group

wherein Y^(1a) is a lower alkylene group, Y^(2a) is a lower alkylenegroup, R^(3a′) is (1) an alkyl group, (2) a cycloalkyl group (3) apiperidyl group optionally having 1 or 2 substituents selected from thegroup consisting of a lower alkyl group, (4) a tetrahydropyranyl group,(5) a lower alkoxycarbonyl lower alkyl group, (6) a lower alkoxy loweralkoxy lower alkyl group (7) an amino lower alkyl group optionallyhaving a lower alkylcarbonyl group, R^(4a) is (1) an alkyl group, or (2)a cycloalkyl group; or a salt thereof.
 5. A pharmaceutical compositioncomprising the heterocyclic compound according to claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent and/or a carrier.
 6. A prophylactic and/ortherapeutic agent for a central neurological disease, comprising theheterocyclic compound according to claim 1 or a pharmaceuticallyacceptable salt thereof as an active ingredient.
 7. The agent accordingto claim 6, wherein the central neurological disease is selected fromthe group consisting of schizophrenia, treatment-resistant, refractoryor chronic schizophrenia, emotional disturbance, psychotic disorder,mood disorder, bipolar disorder, mania, depression, endogenousdepression, major depression, melancholic and treatment-resistantdepression, dysthymic disorder, cyclothymic disorder, anxiety disorder,somatoform disorder, factitious disorder, dissociative disorder, sexualdisorder, eating disorder, sleep disorder, adjustment disorder,substance-related disorder, anhedonia, delirium, Alzheimer's disease,Parkinson disease, cognitive impairment, cognitive impairment associatedwith neurodegenerative diseases, cognitive impairment caused byneurodegenerative diseases, cognitive impairment in schizophrenia,cognitive impairment caused by treatment-resistant, refractory orchronic schizophrenia, vomiting, motion sickness, obesity, migraine,pain, mental retardation, autistic disorder, Tourette's disorder, ticdisorder, attention deficit hyperactivity disorder, conduct disorder andDown's syndrome.
 8. Use of the heterocyclic compound according to claim1 or a pharmaceutically acceptable salt thereof as a medicament.
 9. Amethod of preventing and/or treating a central neurological disease,comprising administering the heterocyclic compound according to claim 1or a pharmaceutically acceptable salt thereof to a human or an animal.10. The method according to claim 9, wherein the central neurologicaldisease is selected from the group consisting of schizophrenia,treatment-resistant, refractory or chronic schizophrenia, emotionaldisturbance, psychotic disorder, mood disorder, bipolar disorder, mania,depression, endogenous depression, major depression, melancholic andtreatment-resistant depression, dysthymic disorder, cyclothymicdisorder, anxiety disorder, somatoform disorder, factitious disorder,dissociative disorder, sexual disorder, eating disorder, sleep disorder,adjustment disorder, substance-related disorder, anhedonia, delirium,Alzheimer's disease, Parkinson disease, cognitive impairment, cognitiveimpairment associated with neurodegenerative diseases, cognitiveimpairment caused by neurodegenerative diseases, cognitive impairment inschizophrenia, cognitive impairment caused by treatment-resistant,refractory or chronic schizophrenia, vomiting, motion sickness, obesity,migraine, pain, mental retardation, autistic disorder, Tourette'sdisorder, tic disorder, attention deficit hyperactivity disorder,conduct disorder and Down's syndrome.
 11. A method of producing aheterocyclic compound represented by the formula (I)

wherein each symbol is as defined in claim 1, or a salt thereof,comprising reacting a compound represented by the formula

wherein X₁ is a halogen atom or a group that causes a substitutionreaction similar to that by a halogen atom, and other symbols are asdefined in claim 1, or a salt thereof, with a compound represented by

wherein Q is as defined in claim 1, or a salt thereof.